PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T16	0-2	Sentence	denotes	1.
T17	3-15	Sentence	denotes	Introduction
T18	16-298	Sentence	denotes	Over the last 20 years, humanity has dealt with three serious coronavirus infection outbreaks, namely severe acute respiratory syndrome coronavirus (SARS-CoV, 2002–2003) [1], Middle East respiratory syndrome coronavirus (MERS-CoV, 2012–2019) [2], and SARS-CoV-2, (2019-present) [3].
T19	299-559	Sentence	denotes	Although it appears that the fatality rates for the first two outbreaks are much higher (9.2% and 37%, respectively) than the ongoing pandemic (~3.3% as of 5 September 2020) [4,5], the ongoing infectious disease of SARS-CoV-2 appears to be far more contagious.
T20	560-728	Sentence	denotes	The ongoing outbreak, widely known as coronavirus disease of 2019 (COVID-19), was recognized by the World Health Organization as a global pandemic on 11 March 2020 [6].
T21	729-864	Sentence	denotes	As of 5 September 2020, there have been more than 26.7 million confirmed cases worldwide with more than 876 thousand global deaths [4].
T22	865-960	Sentence	denotes	Efforts are ongoing to deliver an effective vaccine to protect individuals against the disease.
T23	961-1111	Sentence	denotes	Likewise, potential therapeutics to prevent and/or treat the disease and its complications are being advanced to clinical trials all around the world.
T24	1112-1531	Sentence	denotes	In this direction, effective treatments for COVID-19 patients, particularly those who have the severe version of the disease and become critically ill needing hospitalization, intensive care unit (ICU) admission, and mechanical ventilation, appear to include antiviral drugs as well as anti-inflammatory drugs and anticoagulant drugs to also treat the associated cytokine storm [7] and coagulopathies [8], respectively.
T25	1532-1688	Sentence	denotes	Considering the current clinical guidelines, remdesivir has been recommended for the treatment of COVID-19 in hospitalized patients with severe disease [9].
T26	1689-1809	Sentence	denotes	Furthermore, favipiravir has been approved for the treatment of COVID-19 in the hospital settings in few countries [10].
T27	1810-1978	Sentence	denotes	Moreover, dexamethasone as an anti-inflammatory drug has also been recommended in patients with COVID-19 who require mechanical ventilation or supplemental oxygen [11].
T28	1979-2086	Sentence	denotes	Despite the above recommendations and/or approvals, the need for effective treatment remains largely unmet.
T29	2087-2215	Sentence	denotes	Therefore, a large number of potential therapeutics continue to be developed and others are being advanced into clinical trials.
T30	2216-2349	Sentence	denotes	We recently reviewed the chemical and mechanistic aspects of antiviral drugs that block the early phase of the virus life cycle [12].
T31	2350-2531	Sentence	denotes	In this article, we review the chemical structures and the mechanisms of action of potential antiviral therapeutics that block/inhibit the post-entry stages of the virus life cycle.
T32	2532-2604	Sentence	denotes	We only include those therapeutics that are listed in clinicatrials.gov.
T33	2605-2660	Sentence	denotes	They include both old drugs and new molecular entities.
T34	2661-2743	Sentence	denotes	Many of the potential therapeutics are small molecules and few are macromolecules.
T35	2744-2810	Sentence	denotes	Some of these therapeutics also possess anti-inflammatory effects.
T36	2812-2883	Sentence	denotes	The Life Cycle of SARS-COV-2 and Potential Targets for Drug Development
T37	2884-2977	Sentence	denotes	The life cycle of the virus includes early-stage events and later-stage events (Figure 1a,b).
T38	2978-3123	Sentence	denotes	In the first stage, the virus utilizes its spike (S) protein to bind to angiotensin converting enzyme 2 (ACE2) on the host cell membrane [13,14].
T39	3124-3388	Sentence	denotes	The virus enters the host cell after the spike S protein-ACE2 complex is proteolytically activated by transmembrane protease serine 2 (TMPRSS2) (see (b) in Figure 1), which eventually permits the virus-host cell fusion and the release of the viral RNA genome [15].
T40	3389-3488	Sentence	denotes	Alternatively, the bound virus spike S protein can also be proteolytically activated by furin [16].
T41	3489-3687	Sentence	denotes	Further processing is promoted by cathepsins in (endo)lysosomes to ultimately aid in the viral envelope fusion with the host membranes and the release of the viral genome (see (a) in Figure 1) [17].
T42	3688-3908	Sentence	denotes	The RNA genome of SARS-CoV-2 has more than 29,800 nucleotides which encode for about 29 proteins: nonstructural proteins (NSPs; 16 proteins), structural proteins (4 proteins), and accessory proteins (9 proteins) [18,19].
T43	3909-4089	Sentence	denotes	The structural proteins are spike S protein, envelope (E) and membrane (M) proteins which form the viral envelope, and nucleocapsid (N) protein which binds to the virus RNA genome.
T44	4090-4408	Sentence	denotes	In the post-entry phase of the virus life cycle (Figure 1), the NSPs domain is expressed as two polypeptides which, after processing, produce papain like protease (PLpro) (NSP3), main protease (Mpro) (also known as 3-chymotrypsin-like protease (3CLpro); NSP5) [20], and RNA-dependent RNA polymerase (RdRp; NSP12) [21].
T45	4409-4549	Sentence	denotes	Initial processing of the two polypeptides is promoted by host proteases, and then, is propagated by the action of the viral PLpro and Mpro.
T46	4550-4643	Sentence	denotes	The viral RdRp is also responsible for the replication and amplification of the viral genome.
T47	4644-4894	Sentence	denotes	The viral RNA and the N structural protein are biosynthesized in the host cell cytoplasm, whereas other viral structural proteins including S, M, and E are eventually biosynthesized in the endoplasmic reticulum and transported to the Golgi apparatus.
T48	4895-5066	Sentence	denotes	The viral RNA–N complex and S, M, and E proteins are then assembled in the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) to produce a mature virus particle.
T49	5067-5216	Sentence	denotes	The mature virus is then released from the Golgi apparatus via a budding process and next from the host cells by exocytosis (Figure 1) [12,22,23,24].
T50	5217-5378	Sentence	denotes	Collectively, the goal of antiviral therapeutics is to inhibit one or more events in the life cycle of the virus in order to impede the propagation of infection.
T51	5379-5526	Sentence	denotes	Along these lines, any protein or event in the virus life cycle can be considered as a molecular target for anti-COVID-19 drug development efforts.
T52	5527-5695	Sentence	denotes	In this review, we describe the antiviral agents that are currently being tested in clinical trials to block and/or inhibit the advanced events of the virus life cycle.
T53	5696-5874	Sentence	denotes	Although the majority of the presented antiviral therapeutics target the viral polymerase or the viral proteases, few other therapeutics target other molecular targets (Table 1).
T54	5876-5878	Sentence	denotes	2.
T55	5879-5906	Sentence	denotes	Viral Polymerase Inhibitors
T56	5908-5912	Sentence	denotes	2.1.
T57	5913-5942	Sentence	denotes	Remdesivir (Veklury, GS-5734)
T58	5943-6045	Sentence	denotes	Remdesivir is an adenosine monophosphate derivative and nucleotide-based antiviral prodrug (Figure 2).
T59	6046-6124	Sentence	denotes	Remdesivir received, in May 2020, an emergency use authorization from the U.S.
T60	6125-6262	Sentence	denotes	FDA for the treatment of laboratory-confirmed or suspected COVID-19 illness in children and adults hospitalized with severe disease [25].
T61	6263-6390	Sentence	denotes	The parenterally administered drug is being developed by Gilead Sciences, U.S., and has broad-spectrum antiviral activity [26].
T62	6391-6466	Sentence	denotes	It was first studied in 2016 as a potential treatment for Ebola virus [27].
T63	6467-6635	Sentence	denotes	In addition to its activity against SARS-CoV-2, remdesivir has a potential to treat a variety of infections caused by RNA viruses, including SARS-CoV and MERS-CoV [28].
T64	6636-6773	Sentence	denotes	The drug is metabolized to the pharmacologically active nucleoside triphosphate metabolite after being distributed into cells (Figure 2).
T65	6774-6946	Sentence	denotes	The triphosphate metabolite acts as a competitive inhibitor of RdRp and thus eventually causes chain elongation termination, which decreases the viral RNA replication [29].
T66	6947-7043	Sentence	denotes	The termination is delayed and happens after the addition of more nucleotides (between 3 and 5).
T67	7044-7152	Sentence	denotes	Therefore, remdesivir is described as a direct antiviral agent acting as a delayed chain terminator [30,31].
T68	7153-7230	Sentence	denotes	Importantly, remdesivir avoids proofreading by viral exoribonuclease [28,32].
T69	7231-7346	Sentence	denotes	Currently, remdesivir is being evaluated as a treatment for COVID-19 patients in about 15 studies across the globe.
T70	7347-7528	Sentence	denotes	The drug is being tested alone or in combination with merimepodib (NCT04410354; n = 40), tocilizumab (NCT04409262; REMDACTA; n = 450), or baricitinib (NCT04401579; ACTT2; n = 1034).
T71	7529-7640	Sentence	denotes	In particular, merimepodib is another antiviral agent that is inhibitor of inosine monophosphate dehydrogenase.
T72	7641-7705	Sentence	denotes	The enzyme is required for the synthesis of guanine nucleotides.
T73	7706-7821	Sentence	denotes	Merimepodib consequently inhibits the synthesis of DNA and RNA, leading to antiviral and immunosuppressive effects.
T74	7822-7926	Sentence	denotes	Thus, remdesivir and merimepodib is a dual-acting antiviral combination with immunosuppressive activity.
T75	7927-8074	Sentence	denotes	Remdesivir itself demonstrated in vitro activity against Vero E6 cells infected with SARS-CoV-2 with an EC50 value of 0.77 µM (CC50 > 100 µM) [33].
T76	8075-8272	Sentence	denotes	Remdesivir also exhibited in vitro activity against SARS-CoV and MERS-CoV in multiple in vitro systems, including primary human airway epithelial cell cultures with sub-micromolar IC50 values [28].
T77	8273-8475	Sentence	denotes	Remdesivir was also effective against pre-pandemic bat-CoVs, bat-CoVs, and contemporary circulating human coronaviruses in primary human lung cells suggesting a broad-spectrum anti-coronavirus activity.
T78	8476-8704	Sentence	denotes	In a mouse model of SARS-CoV, the prophylactic and early therapeutic use of remdesivir significantly decreased the lung viral load and improved the respiratory functions as well as the overall clinical signs of the disease [28].
T79	8705-8844	Sentence	denotes	Furthermore, remdesivir with interferon (INF)-b demonstrated better antiviral activity compared to lopinavir/ritonavir with INF-b in vitro.
T80	8845-9061	Sentence	denotes	Compared to lopinavir/ritonavir/INF-b, the prophylactic and therapeutic use of remdesivir also more effectively diminished the pulmonary viral loads and improved the pulmonary function in mice model of MERS-CoV [34].
T81	9062-9206	Sentence	denotes	The efficacy of the prophylactic and therapeutic use of remdesivir was also demonstrated in the rhesus macaque model of MERS-CoV infection [35].
T82	9207-9364	Sentence	denotes	Very recently, remdesivir was also shown to inhibit SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM).
T83	9365-9562	Sentence	denotes	In mice infected with a chimeric SARS-CoV encoding RdRp, therapeutic administration of remdesivir diminished lung viral load and improved pulmonary function compared with vehicle-treated mice [36].
T84	9563-9916	Sentence	denotes	As far as clinical trials in humans, a randomized, placebo-controlled, double-blind trial in hospitalized adults (n = 236) with severe COVID-19 in China initially revealed that the median time to improvement was not substantially different in the remdesivir group (200 mg on the first day, and then 100 mg/day for 9 days) from that of the placebo group.
T85	9917-9976	Sentence	denotes	The mortality rate was also similar in the two groups [37].
T86	9977-10040	Sentence	denotes	Yet, the trial was criticized for being insufficiently powered.
T87	10041-10319	Sentence	denotes	Later, a phase 3 randomized, open-label trial in adults (n = 397) hospitalized with severe COVID-19 sponsored by Gilead revealed that the time to clinical improvement for 50% of patients was 10 days in the 5-day treatment group relative to 11 days in the 10-day treatment group.
T88	10320-10412	Sentence	denotes	The dose regimen used was 200 mg on day 1, followed by 100 mg/day for total of 5 or 10 days.
T89	10413-10544	Sentence	denotes	At day 14, about 64.5% of the patients in the 5-day group and 53.8% of the patients in the 10-day group achieved clinical recovery.
T90	10545-10703	Sentence	denotes	Patients treated with remdesivir within 10 days of symptoms onset achieved better outcomes relative to those treated after more than 10 days of symptoms [38].
T91	10704-10805	Sentence	denotes	Similar results were obtained in hospitalized adults (n = 1600) with moderate COVID-19 (NCT04292730).
T92	10806-10948	Sentence	denotes	In an uncontrolled study of hospitalized COVID-19 patients (n = 61), most patients needed less oxygen support after receiving remdesivir [39].
T93	10949-11040	Sentence	denotes	Importantly, a phase 3 adaptive, randomized, placebo-controlled study sponsored by the U.S.
T94	11041-11406	Sentence	denotes	National Institute of Allergy and Infectious Diseases (NIAID) in hospitalized adults (n = 1063) indicated that: (a) the patients in the remdesivir group had shorter median time to recovery (11 days) than the patients in the placebo group (15 days) and (b) remdesivir may decrease the mortality rate from 11.6% in the placebo group to 8% in the treatment group [40].
T95	11407-11469	Sentence	denotes	As of now, the COVID-19 Treatment Guidelines Panel of the U.S.
T96	11470-11696	Sentence	denotes	National Institute of Health recommends remdesivir for the treatment of COVID-19 in hospitalized patients with severe disease (requiring supplemental oxygen or on mechanical ventilation or extracorporeal membrane oxygenation).
T97	11697-11861	Sentence	denotes	The Panel also indicates that there are no sufficient data to recommend either for or against the use of remdesivir in patients with mild or moderate COVID-19 [41].
T98	11862-11879	Sentence	denotes	Of note, the U.S.
T99	11880-12084	Sentence	denotes	FDA warns against the concomitant use of remdesivir and chloroquine or hydroxychloroquine owing to in vitro evidence which suggests that chloroquine blocks the intracellular activation of remdesivir [42].
T100	12085-12262	Sentence	denotes	Moreover, data from the manufacturer’s compassionate use program suggested no safety concerns were identified for remdesivir in pediatric, pregnant, or postpartum patients [43].
T101	12264-12268	Sentence	denotes	2.2.
T102	12269-12304	Sentence	denotes	Galidesivir (Immucillin-A, BCX4430)
T103	12305-12418	Sentence	denotes	Galidesivir is an adenosine nucleoside analog (Figure 3) that is an active site inhibitor of RdRp (EC50 < 50 µM).
T104	12419-12558	Sentence	denotes	Similar to remdesivir, it is a prodrug that is metabolized by cellular kinases to the corresponding active form of nucleoside triphosphate.
T105	12559-12722	Sentence	denotes	The triphosphate form binds to the active site of the viral enzyme and gets incorporated into the growing viral RNA chain resulting in premature chain termination.
T106	12723-12884	Sentence	denotes	The drug is being developed by BioCryst, U.S., and being tested in a phase 1 clinical trial for COVID-19 or Yellow Fever in Brazil in collaboration with the U.S.
T107	12885-12928	Sentence	denotes	NIAID (NCT03891420; n = 132) [44,45,46,47].
T108	12929-13128	Sentence	denotes	The drug is used parenterally and has demonstrated a broad-spectrum, showing in vitro antiviral activity against at least 20 RNA viruses across eight different virus families including coronaviruses.
T109	13129-13280	Sentence	denotes	In animal studies, the drug was effective in protecting against dangerous viruses such as Zika, Yellow Fever, Marburg, and Ebola viruses [44,45,46,47].
T110	13282-13286	Sentence	denotes	2.3.
T111	13287-13307	Sentence	denotes	Ribavirin (Virazole)
T112	13308-13398	Sentence	denotes	It is an open-ring analog of guanosine nucleoside (Figure 3) that was approved by the U.S.
T113	13399-13465	Sentence	denotes	FDA in 1985 for the treatment of respiratory syncytial virus [48].
T114	13466-13579	Sentence	denotes	It is also used systemically for chronic hepatitis C virus (HCV) infection [49] and viral hemorrhagic fever [50].
T115	13580-13666	Sentence	denotes	The drug possesses broad-spectrum antiviral activity against both RNA and DNA viruses.
T116	13667-13858	Sentence	denotes	To exert its antiviral activity, the drug is to be activated by phosphorylation to generate the triphosphate nucleotide that acts as an inhibitor of RNA synthesis and viral mRNA capping [51].
T117	13859-13956	Sentence	denotes	Other mechanisms have also been proposed to account for its broad spectrum of antiviral activity.
T118	13957-14159	Sentence	denotes	Inhibition of host inosine monophosphate dehydrogenase by ribavirin-monophosphate and the resulting depletion of guanosine triphosphate (GTP) pool has been put forward to be another mechanism of action.
T119	14160-14270	Sentence	denotes	Decreased intracellular GTP pool decreases viral protein synthesis and limits the replication of viral genome.
T120	14271-14377	Sentence	denotes	Ribavirin is also a mutagen that leads to defective virions [52] and it has immunomodulatory actions [53].
T121	14378-14510	Sentence	denotes	Yet, the drug has a U.S. boxed warning pertaining to the risk of hemolytic anemia and potential complications during pregnancy [54].
T122	14511-14603	Sentence	denotes	Ribavirin is currently being evaluated in few trials for the treatment of COVID-19 patients.
T123	14604-14789	Sentence	denotes	It is being tested alone (NCT04356677; n = 50) or in combination with nitazoxanide and ivermectin (NCT04392427; n = 100) or with lopinavir/ritonavir and INF β-1b (NCT04276688; n = 127).
T124	14790-14893	Sentence	denotes	Recent computational work has shown that ribavirin binds with high affinity to RdRp of SARS-CoV-2 [55].
T125	14894-15000	Sentence	denotes	Furthermore, the MERS-CoV rhesus macaque model revealed promising results for ribavirin and IFN-α 2b [56].
T126	15001-15137	Sentence	denotes	Nevertheless, mixed results came out of treating MERS-CoV infections with a combination of ribavirin and IFNs (IFN-β1 or IFN-α 2a) [57].
T127	15138-15359	Sentence	denotes	Results from the in vitro testing of ribavirin in Vero E6 cells also indicated that the replication and/or the cellular spread of SARS-CoV was not inhibited at concentrations known to inhibit other sensitive viruses [58].
T128	15360-15742	Sentence	denotes	Interestingly, a recent open-label randomized controlled trial (NCT04276688; n = 127) indicated that early triple antiviral therapy of INF-β 1b, ribavirin, and lopinavir/ritonavir was safe and superior to lopinavir/ritonavir alone in alleviating the symptoms and shortening the duration of viral shedding and hospitalization in COVID-19 patients with mild to moderate symptoms [59].
T129	15744-15748	Sentence	denotes	2.4.
T130	15749-15780	Sentence	denotes	Clevudine (Levovir and Revovir)
T131	15781-15912	Sentence	denotes	It a thymidine nucleoside analog (Figure 3) that was approved in Korea for the treatment of hepatitis B virus (HBV) infection [60].
T132	15913-16049	Sentence	denotes	Similar to previous agents, it is a prodrug that requires phosphorylation to form the corresponding active nucleotide, the triphosphate.
T133	16050-16201	Sentence	denotes	Mechanistically, the triphosphate active form appears to noncompetitively inhibit the HBV reverse transcriptase protein priming and DNA synthesis [61].
T134	16202-16370	Sentence	denotes	Importantly, although clevudine showed a potent antiviral response, its long-term use for more than a year led to the development of viral resistance and myopathy [60].
T135	16371-16471	Sentence	denotes	The drug is being evaluated in a phase 2 as a treatment for COVID-19 in Korea (NCT04347915; n = 60).
T136	16473-16477	Sentence	denotes	2.5.
T137	16478-16567	Sentence	denotes	Emtricitabine (Emtriva) in Combination with Tenofovir Disoproxil or Tenofovir Alafenamide
T138	16568-16721	Sentence	denotes	Emtricitabine is a cytosine nucleoside analog (Figure 3) that is a competitive inhibitor of human immunodeficiency virus-1 (HIV-1) reverse transcriptase.
T139	16722-16810	Sentence	denotes	It is metabolized by cellular kinases-mediated phosphorylation to the triphosphate form.
T140	16811-17038	Sentence	denotes	Emtricitabine triphosphate is the active form that blocks the HIV replication by terminating its genetic chain elongation, and thus, it prevents the generation of complementary DNA from the viral RNA and reduces the viral load.
T141	17039-17078	Sentence	denotes	The drug was first approved by the U.S.
T142	17079-17149	Sentence	denotes	FDA as an orally bioavailable, once-daily antiretroviral drug in 2003.
T143	17150-17257	Sentence	denotes	It is now used in combination with other antiretroviral drugs for the treatment of HIV-1 infection [62,63].
T144	17258-17484	Sentence	denotes	Combinations with tenofovir disoproxil fumarate (Truvada), tenofovir alafenamide (Descovy; 2016), rilpivirine, and tenofovir alafenamide (Odefsey; 2016), or bictegravir and tenofovir alafenamide (Biktarvy; 2018) are available.
T145	17485-17743	Sentence	denotes	In particular, tenofovir disoproxil (Viread; 2001) is an adenine-based acyclic nucleotide analog (Figure S1) that, following activation, acts as a competitive inhibitor of reverse transcriptase, and subsequently, it leads to DNA chain elongation termination.
T146	17744-18068	Sentence	denotes	Activation of the drug starts with the hydrolysis of the external esters followed by spontaneous release of carbon dioxide and formaldehyde to form the corresponding tenofovir, a nucleoside monophosphate, which subsequently undergoes two phosphorylation steps to form tenofovir diphosphate, the active drug (Figure S1) [64].
T147	18069-18110	Sentence	denotes	It was first approved in 2001 by the U.S.
T148	18111-18197	Sentence	denotes	FDA and is prescribed for the oral treatment of HIV-1 and chronic HBV infections [65].
T149	18198-18381	Sentence	denotes	It is also available in many other combinations with emtricitabine, lamivudine (Cimduo; 2018), doravirine and lamivudine (Delstrigo; 2018), and efavirenz and lamivudine (Symfi; 2018).
T150	18382-18660	Sentence	denotes	The efficacy of emtricitabine and tenofovir disoproxil as a prophylactic combination against SARS-CoV-2 infection is being evaluated in a large randomized, double-blind, controlled with placebo clinical trial for health care providers exposed to COVID-19 patients (NCT04334928).
T151	18661-18833	Sentence	denotes	The two drugs have been reported by a recent computational work as potential inhibitors of RdRp of SARS-CoV-2 [55,66], yet this potential is to be experimentally confirmed.
T152	18834-19050	Sentence	denotes	Likewise, tenofovir alafenamide (Vemlidy; 2016) is an adenine-based acyclic nucleotide analog that, following activation, acts as a competitive inhibitor of reverse transcriptase and DNA chain elongation termination.
T153	19051-19229	Sentence	denotes	The activation of the drug is, however, different and it usually takes place in infected cells by a series of bio-transformations similar to those of remdesivir (Figure S2) [67].
T154	19230-19446	Sentence	denotes	The main advantage of the prodrug, relative to the former prodrug, is that it increases the drug’s oral bioavailability, intestinal diffusion, selectivity of targeting the infected cells, and intracellular half-life.
T155	19447-19528	Sentence	denotes	It also decreases the potential renal toxicity of the monophosphate intermediate.
T156	19529-19589	Sentence	denotes	Tenofovir alafenamide was first approved in 2016 by the U.S.
T157	19590-19657	Sentence	denotes	FDA and is prescribed for the oral treatment of HBV infection [68].
T158	19658-19896	Sentence	denotes	It is also available in many other combinations with emtricitabine (Descovy; 2016), bictegravir and emtricitabine (Biktarvy; 2018), emtricitabine and rilpivirine (Odefsey; 2016), and darunavir/cobicistat and emtricitabine (Symtuza; 2018).
T159	19897-20186	Sentence	denotes	The efficacy of emtricitabine and tenofovir alafenamide as a prophylactic combination against SARS-CoV-2 infection is being evaluated in a large randomized, double-blind, controlled with placebo clinical trial for health care providers exposed to COVID-19 patients (NCT04405271; n = 1378).
T160	20188-20192	Sentence	denotes	2.6.
T161	20193-20220	Sentence	denotes	Favipiravir (Avigan, T-705)
T162	20221-20283	Sentence	denotes	Favipiravir was originally developed by Fujifilm group, Japan.
T163	20284-20376	Sentence	denotes	It is a pyrazine-carboxamide derivative (Figure 4) with a broad-spectrum antiviral activity.
T164	20377-20443	Sentence	denotes	It selectively and potently inhibits the RdRp of RNA viruses [69].
T165	20444-20520	Sentence	denotes	Favipiravir is a prodrug that requires bioactivation in host-infected cells.
T166	20521-20575	Sentence	denotes	Its active form is favipiravir-ribose-5′-triphosphate.
T167	20576-20787	Sentence	denotes	The first step in the formation of the active species is potentially catalyzed by human hypoxanthine guanine phosphoribosyl-transferase [70], which converts favipiravir into ribose-5′-monophosphate intermediate.
T168	20788-20954	Sentence	denotes	The latter intermediate undergoes two phosphorylation steps mediated by the action of host kinases leading to the formation of the ribose-5′-triphosphate active form.
T169	20955-21094	Sentence	denotes	Favipiravir is effective against several strains of influenza viruses, including those that are resistant to existing anti-influenza drugs.
T170	21095-21266	Sentence	denotes	Favipiravir also showed an antiviral activity in experimental animals against other RNA viruses, including arenaviruses, alphaviruses, bunyaviruses, and flaviviruses [71].
T171	21267-21393	Sentence	denotes	Furthermore, preliminary results also indicated that favipiravir potentially possesses a moderate activity against Ebola [72].
T172	21394-21789	Sentence	denotes	Importantly, a recent nonrandomized, open-label study in patients (n = 80) with non-severe COVID-19 showed that favipiravir (1600 mg orally twice daily on the first day, then 600 mg orally twice daily for thirteen days) with INF-α had significantly better therapeutic effects on SARS-CoV-2 infection, in terms of disease progression and viral clearance, than lopinavir/ritonavir with INF-α [73].
T173	21790-22263	Sentence	denotes	Furthermore, an open-label, prospective, randomized, multicenter study in adults (n = 236) with COVID-19 pneumonia in China revealed that favipiravir (1600 mg orally twice daily on the first day, then 600 mg orally twice daily for 7–10 days) was associated with a higher 7-day clinical recovery rate compared to a control group treated with umifenovir, a potential inhibitor of the membrane fusion stage during the virus infection, (200 mg three times daily for 7–10 days).
T174	22264-22447	Sentence	denotes	The 7-day clinical recovery rate in patients with moderate COVID-19 pneumonia was 71% in the favipiravir-treated patients, whereas the rate was 56% in the umifenovir-treated patients.
T175	22448-22582	Sentence	denotes	Likewise, the 7-day clinical recovery rate in patients with severe to critical COVID-19 pneumonia was 6% versus 0%, respectively [74].
T176	22583-22779	Sentence	denotes	Currently, favipiravir is being studied alone or in combination with tocilizumab, hydroxychloroquine, or oseltamivir for the treatment of COVID-19 in more than 23 clinical trials across the world.
T177	22780-22969	Sentence	denotes	As of now, favipiravir is not available in the U.S. or European countries, perhaps because the animal experiments showed that the antiviral agent can be associated with teratogenic effects.
T178	22970-23049	Sentence	denotes	Favipiravir is contraindicated in women with known or suspected pregnancy [75].
T179	23050-23107	Sentence	denotes	Favipiravir is also associated with QT prolongation [76].
T180	23108-23263	Sentence	denotes	It is currently approved to treat novel or re-emerging influenza outbreaks in China and Japan, and it is available as an oral solid dosage form [73,74,76].
T181	23265-23269	Sentence	denotes	2.7.
T182	23270-23276	Sentence	denotes	AT-527
T183	23277-23501	Sentence	denotes	It is an investigational, orally active, purine nucleotide prodrug (Figure S3), which has exhibited antiviral activity against many single-stranded, enveloped RNA viruses, including human flaviviruses and coronaviruses [77].
T184	23502-23546	Sentence	denotes	It is a potent inhibitor of viral RdRp [78].
T185	23547-23689	Sentence	denotes	Following oral administration as hemi-sulfate salt, the drug gets converted to the monophosphate form via multiple metabolic activation steps.
T186	23690-23830	Sentence	denotes	The first step is catalyzed by the action of human carboxylesterase 1 (CES1) and/or cathepsin A (CatA) to produce the L-alanyl intermediate.
T187	23831-23996	Sentence	denotes	Spontaneous hydrolysis followed by histidine triad nucleotide-binding protein 1 (HINT1)-mediated hydrolysis results in the formation of the monophosphate metabolite.
T188	23997-24303	Sentence	denotes	Then, the monophosphate is transformed to guanosine analog by adenosine deaminase like protein 1 (ADALP1) and further phosphorylated by guanylate kinase 1 (GUK1) and nucleoside diphosphate kinase (NDPK) to the pharmacologically active form of AT-527 diphosphate (also reported as AT-9010) (Figure S3) [78].
T189	24304-24448	Sentence	denotes	The safety, pharmacokinetics, and antiviral activity of AT-527 was earlier established in HCV-infected subjects with and without cirrhosis [79].
T190	24449-24655	Sentence	denotes	The drug is currently being evaluated in a phase 2 double-blind, randomized, placebo-controlled study to determine its efficacy and safety in patients with moderate COVID-19 symptoms (NCT04396106; n = 190).
T191	24657-24661	Sentence	denotes	2.8.
T192	24662-24671	Sentence	denotes	EIDD-2801
T193	24672-24744	Sentence	denotes	It is the isopropyl-ester prodrug of β-D-N4-hydroxycytidine (Figure 5A).
T194	24745-24875	Sentence	denotes	The prodrug has improved oral bioavailability as it avoids phosphorylation of the N4-hydroxyl group in the gastrointestinal tract.
T195	24876-25038	Sentence	denotes	It is hydrolyzed in vivo to release the parent (EIDD-1931), which distributes into tissues, and upon tri-phosphorylation, it becomes the active triphosphate form.
T196	25039-25295	Sentence	denotes	The tri-phosphorylated form has a broad-spectrum antiviral activity against various RNA viruses, including influenza, Ebola, Venezuelan equine encephalitis virus, MERS-CoV, SARS-CoV, SARS-CoV-2 and related zoonotic group 2b or 2c bat coronaviruses [80,81].
T197	25296-25402	Sentence	denotes	It also demonstrated increased potency against a coronavirus with resistance mutations to remdesivir [82].
T198	25403-25569	Sentence	denotes	By the action of RdRp, the active form is incorporated into the genome of RNA viruses, leading to the accumulation of mutations known as viral error catastrophe [80].
T199	25570-25752	Sentence	denotes	The active form exists in two forms (Figure 5B): the oxime form which mimics uridine and pairs with adenosine, while the other tautomer mimics cytidine and pairs with guanosine [81].
T200	25753-25920	Sentence	denotes	In mice infected with MERS-CoV or SARS-CoV, EIDD-2801 administration was found to diminish the virus titer and body weight loss and to improve pulmonary function [80].
T201	25921-26049	Sentence	denotes	Reduced MERS-CoV yields in vitro and in vivo was because of the increase in transition mutation frequency in only the viral RNA.
T202	26050-26117	Sentence	denotes	The drug produced similar results in human airway epithelial cells.
T203	26118-26192	Sentence	denotes	The drug showed similar results as a prophylactic and as a treatment [80].
T204	26193-26501	Sentence	denotes	The drug was developed at the Emory Institute for Drug Development and it was tested in a phase 1 randomized, double-blind, placebo-controlled, first-in-human study designed to evaluate its safety, tolerability, and pharmacokinetics following oral administration to healthy volunteers (NCT04392219; n = 130).
T205	26502-26614	Sentence	denotes	It is now being tested in two phase 2 trials in COVID-19 patients (NCT04405570; n = 44 and NCT04405739; n = 60).
T206	26616-26618	Sentence	denotes	3.
T207	26619-26644	Sentence	denotes	Viral Protease Inhibitors
T208	26646-26650	Sentence	denotes	3.1.
T209	26651-26680	Sentence	denotes	Lopinavir/Ritonavir (Kaletra)
T210	26681-26830	Sentence	denotes	Lopinavir (Figure 6) is an orally bioavailable, small peptidomimetic antiretroviral agent that acts as an HIV-1 aspartate competitive inhibitor [83].
T211	26831-26966	Sentence	denotes	The drug inhibits the cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV.
T212	26967-27061	Sentence	denotes	The inhibition eventually results in the formation of immature, noninfectious viral particles.
T213	27062-27095	Sentence	denotes	The drug was approved by the U.S.
T214	27096-27203	Sentence	denotes	FDA in combination with ritonavir (Figure 6), which is another antiretroviral aspartate protease inhibitor.
T215	27204-27406	Sentence	denotes	Ritonavir does not only provide an additive effective, but it is also a pharmacokinetic booster, i.e., it inhibits the CYP3A-mediated metabolism of lopinavir and thus increases its plasma level [83,84].
T216	27407-27741	Sentence	denotes	Currently, lopinavir/ritonavir is being evaluated for the treatment of SARS-CoV-2 patients in more than 35 interventional trials alone or in conjugation with hydroxychloroquine, inhaled INF-α, INF-β 1b and hydroxychloroquine, or oseltamivir (an inhibitor of neuraminidase in influenza virus) (for details refer to clinicaltrials.gov).
T217	27742-27810	Sentence	denotes	The rationale for using lopinavir is attributed to multiple studies.
T218	27811-27941	Sentence	denotes	Lopinavir exhibited an antiviral activity against SARS-CoV-2 virus in Vero E6 cells with an estimated EC50 value of 26.63 μM [85].
T219	27942-28086	Sentence	denotes	Computational studies have also suggested that lopinavir may inhibit the viral main protease Mpro, perhaps by targeting its active site [86,87].
T220	28087-28177	Sentence	denotes	Earlier, lopinavir exhibited in vitro activity against SARS-CoV-1 and MERS-CoV [88,89,90].
T221	28178-28268	Sentence	denotes	It also showed beneficial effects in animal studies for the treatment of MERS-CoV [91,92].
T222	28269-28430	Sentence	denotes	Furthermore, there is an evidence of some clinical benefit for lopinavir/ritonavir when used with ribavirin and/or INFs against MERS-CoV and SARS-CoV [88,93,94].
T223	28431-28590	Sentence	denotes	Yet, coronavirus proteases, including Mpro, do not have a C2-symmetric protein architecture which is the target of lopinavir and all HIV-1 protease inhibitors.
T224	28591-28698	Sentence	denotes	This subsequently sheds doubts on the prospect of HIV-1 aspartate protease inhibitors in treating COVID-19.
T225	28699-28963	Sentence	denotes	In this direction, a randomized, open-label trial in China in COVID-19 patients (n = 199), who were hospitalized with severe illness, compared lopinavir/ritonavir (400 mg/100 mg twice a day for 14 days) along with the standard care to the standard care alone [94].
T226	28964-29261	Sentence	denotes	The trial found that the time to achieve clinical improvement was similar in the two groups and that no statistically significant improvement, with respect to the viral load, oxygen therapy duration, hospitalization duration, or time to death, was achieved by the use of the drug combination [95].
T227	29262-29411	Sentence	denotes	Furthermore, a retrospective cohort study in China evaluated the use of lopinavir/ritonavir with or without umifenovir in COVID-19 patients (n = 16).
T228	29412-29606	Sentence	denotes	On the seventh day, SARS-CoV-2 was not detected in the nasopharyngeal specimens of 35% of lopinavir/ritonavir-treated patients compared to 75% of lopinavir/ritonavir/umifenovir-treated patients.
T229	29607-29702	Sentence	denotes	Chest computerized tomography scans were also better in the latter group (29% versus 69%) [96].
T230	29703-29988	Sentence	denotes	Moreover, a randomized, open-label trial in COVID-19 adults (n = 127) with mild to moderate symptoms in Hong Kong suggested that adding ribavirin and INF-β-1b to lopinavir/ritonavir increased the efficacy of the treatment when it was initiated within 7 days of the symptoms onset [59].
T231	29989-30117	Sentence	denotes	Other studies also suggested a limited benefit of lopinavir/ritonavir with or without INFs in patients with COVID-19 [97,98,99].
T232	30118-30451	Sentence	denotes	Recently, a small, randomized study in hospitalized COVID-19 adults (n = 22) in China compared lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily for 10 days) against chloroquine (500 mg twice daily for 10 days) and found that chloroquine was linked to a shorter time to RT-PCR conversion and a faster recovery [100].
T233	30453-30457	Sentence	denotes	3.2.
T234	30458-30490	Sentence	denotes	Darunavir/Cobicistat (Prezcobix)
T235	30491-30610	Sentence	denotes	Darunavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease [101,102].
T236	30611-30837	Sentence	denotes	In addition to the active site, it has been reported that the flexible darunavir binds to another site on the surface of the enzyme, which accounts for its resilience against potential mutations in the targeted protease [103].
T237	30838-30880	Sentence	denotes	Darunavir was approved in 2015 by the U.S.
T238	30881-30967	Sentence	denotes	FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat.
T239	30968-31155	Sentence	denotes	Although structurally similar to ritonavir, cobicistat lacks antiviral activity due to the lack of the central phenyl-propanol moiety, a key structural feature of HIV protease inhibitors.
T240	31156-31251	Sentence	denotes	Darunavir/cobicistat is under clinical investigation for the treatment of SARS-CoV-2 infection.
T241	31252-31407	Sentence	denotes	This is potentially attributed to darunavir ability to in vitro inhibit SARS-CoV-2 in Vero E6 cells, albeit at high concentrations (EC50 = 46.41 µM) [104].
T242	31408-31512	Sentence	denotes	Mechanistically, this could be because darunavir potentially inhibits 3CLpro and/or PLpro of SARS-CoV-2.
T243	31513-31581	Sentence	denotes	The two enzymes are important for the viral glycoprotein processing.
T244	31582-31743	Sentence	denotes	However, in another in vitro study, darunavir/cobicistat demonstrated no activity against SARS-CoV-2 at clinically relevant concentrations in Caco-2 cells [105].
T245	31744-31900	Sentence	denotes	Furthermore, the results from a randomized controlled trial in China showed that darunavir/cobicistat was not effective in treating COVID-19 patients [106].
T246	31901-32198	Sentence	denotes	Regardless, darunavir is being tried in about three trials in combination with cobicistat (NCT04252274; n = 30), ritonavir/hydroxychloroquine (NCT04435587; n = 80), ritonavir/oseltamivir, ritonavir/oseltamivir/hydroxychloroquine, or ritonavir/favipiravir/hydroxychloroquine (NCT04303299; n = 320).
T247	32199-32280	Sentence	denotes	TMC310911 (also known as ASC-09) (Figure 6) is structurally similar to darunavir.
T248	32281-32367	Sentence	denotes	It is HIV-1 aspartate protease competitive inhibitor with improved antiviral activity.
T249	32368-32562	Sentence	denotes	TMC310911 has potent activity against the wild-type HIV-1 and against an extended spectrum of recombinant HIV-1 clinical isolates, including multiple protease inhibitors-resistant strains [107].
T250	32563-32651	Sentence	denotes	Similar to darunavir, it was evaluated with the pharmacokinetic booster ritonavir [108].
T251	32652-32751	Sentence	denotes	Currently, it is being tested in two clinical trials in China in patients infected with SARS-CoV-2.
T252	32752-32861	Sentence	denotes	It is being tested in combination with ritonavir (NCT04261907; n = 160) or oseltamivir (NCT04261270; n = 60).
T253	32862-33028	Sentence	denotes	In a recent computational exercise, TMC-310911 was reported as a potential inhibitor of Mpro of SARS-CoV-2 [66], yet this potential is to be experimentally confirmed.
T254	33030-33034	Sentence	denotes	3.3.
T255	33035-33055	Sentence	denotes	Atazanavir (Reyataz)
T256	33056-33166	Sentence	denotes	Atazanavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease.
T257	33167-33210	Sentence	denotes	Atazanavir was approved in 2003 by the U.S.
T258	33211-33357	Sentence	denotes	FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat (combination is being marketed under the name Evotaz; 2015).
T259	33358-33620	Sentence	denotes	Currently, it is being evaluated alone (NCT04468087; n = 189) or in combination with NA-831 (neuroprotective agent; traneurocin) or dexamethasone for the treatment of COVID-19 infection (NCT04452565; n = 525) or with nitazoxanide/ritonavir (NCT04459286; n = 98).
T260	33621-33808	Sentence	denotes	The drug alone or in combination with ritonavir demonstrated in vitro activity against SARS-CoV-2 in Vero E6 cells, human epithelial pulmonary cells (A549), and human monocytes [109,110].
T261	33809-33879	Sentence	denotes	In these studies, atazanavir has been identified as inhibitor of Mpro.
T262	33880-34005	Sentence	denotes	The drug and its combination have been projected to be 10-fold more potent than lopinavir and its combination with ritonavir.
T263	34006-34091	Sentence	denotes	The drug also inhibited the virus-induced enhancement of IL-6 and TNF-α levels [109].
T264	34092-34248	Sentence	denotes	In a separate computational study, atazanavir was reported as a potential inhibitor of SARS-CoV-2 helicase, a viral enzyme that unwinds nucleic acids [111].
T265	34250-34254	Sentence	denotes	3.4.
T266	34255-34275	Sentence	denotes	Danoprevir/Ritonavir
T267	34276-34388	Sentence	denotes	Danoprevir (Ganovo) is an orally bioavailable 15-membered macrocyclic peptidomimetic antiviral drug (Figure S4).
T268	34389-34471	Sentence	denotes	It is an inhibitor of NS3/4A HCV protease, an important processing enzyme complex.
T269	34472-34533	Sentence	denotes	It inhibits the protease with an IC50 value of 0.29 nM [112].
T270	34534-34597	Sentence	denotes	It was approved in China in 2018 to treat chronic HCV patients.
T271	34598-34681	Sentence	denotes	At higher concentrations, it also appears to inhibit the aspartate protease of HIV.
T272	34682-34821	Sentence	denotes	The NS3/4A protease of HCV is claimed to share a certain level of structural and/or functional similarity to the protease(s) of SARS-CoV-2.
T273	34822-34933	Sentence	denotes	Thus, HCV protease inhibitors, including danoprevir, have been proposed as potential therapeutics for COVID-19.
T274	34934-35230	Sentence	denotes	This has also been supported by computational work which indicated that HCV protease inhibitors have high binding affinity to 3CLpro of SARS-CoV-2 [113] and by in vitro and clinical studies which showed that patients with SARS-CoV or MERS-CoV may benefit from HCV protease inhibitors [88,90,114].
T275	35231-35433	Sentence	denotes	Currently, danoprevir in combination with ritonavir, is being evaluated in two clinical trials (NCT04345276; n = 10) and (with nebulized INF; NCT04291729; n = 11) for the treatment of COVID-19 patients.
T276	35434-35610	Sentence	denotes	As mentioned earlier, ritonavir is an antiviral and pharmacokinetic booster that extends the systemic exposure of patients to potential therapeutic concentration of danoprevir.
T277	35611-35809	Sentence	denotes	In fact, a recent clinical study results under review has indicated that danoprevir/ritonavir combination alleviated the symptoms in COVID-patients and accelerated their recovery in 4–12 days [115].
T278	35811-35815	Sentence	denotes	3.5.
T279	35816-35837	Sentence	denotes	Maraviroc (Selzentry)
T280	35838-36123	Sentence	denotes	It is a small, synthetic, azabicyclic molecule (Figure S4) that exhibits antiretroviral activity by blocking the interaction between HIV-1 glycoprotein 120 and chemokine receptor 5 (C-C motif receptor 5), on human CD4-presenting cells, that is necessary for HIV-1 to enter cells [116].
T281	36124-36157	Sentence	denotes	The drug was approved by the U.S.
T282	36158-36201	Sentence	denotes	FDA in 2007 as an oral treatment for HIV-1.
T283	36202-36332	Sentence	denotes	The drug is currently being evaluated in three clinical trials (NCT04441385, NCT04435522, and NCT04475991) for COVID-19 treatment.
T284	36333-36418	Sentence	denotes	Recently, it was shown that maraviroc may act as a potential inhibitor of Mpro [117].
T285	36419-36632	Sentence	denotes	However, it appears that it is more realistic to assume that the drug is a viral entry inhibitor and potentially acts by blocking the interaction between the viral spike S protein and the host ACE2 receptor [118].
T286	36634-36636	Sentence	denotes	4.
T287	36637-36667	Sentence	denotes	Miscellaneous Antiviral Agents
T288	36669-36673	Sentence	denotes	4.1.
T289	36674-36700	Sentence	denotes	Selinexor (Xpovio, KPT330)
T290	36701-36797	Sentence	denotes	Selinexor is bis(trifluoromethyl)phenyl-triazole-based antineoplastic small molecule (Figure 7).
T291	36798-36839	Sentence	denotes	It was first approved in 2019 by the U.S.
T292	36840-36931	Sentence	denotes	FDA and is being prescribed with dexamethasone for refractory or relapsed multiple myeloma.
T293	36932-37073	Sentence	denotes	Selinexor is an orally bioavailable, selective inhibitor of chromosome region maintenance 1 (CRM1) protein (also known as exportin 1 (XPO1)).
T294	37074-37200	Sentence	denotes	CRM1 is the main export factor that shuttles nuclear proteins to the cytoplasm and is typically overexpressed in cancer cells.
T295	37201-37325	Sentence	denotes	Its selective inhibition can assist in restoring the endogenous tumor-suppressing processes so as to eliminate cancer cells.
T296	37326-37609	Sentence	denotes	Specifically, selinexor selectively and irreversibly modifies the essential Cys528 residue in CRM1, and thus, it blocks CRM1-mediated nuclear export of cargo proteins such as tumor suppressor proteins (p21, p53, pRB, BRCA1/2, FOXO, and others) from the cell nucleus to the cytoplasm.
T297	37610-37685	Sentence	denotes	This leads to the accumulation of tumor suppressor proteins in the nucleus.
T298	37686-37837	Sentence	denotes	It also results in decreased levels of oncoproteins, cell cycle arrest, and apoptosis of cancer cells without affecting the normal cells [119,120,121].
T299	37838-38088	Sentence	denotes	Considering the current viral pandemic, CRM1 has been put forward as a facilitator of the export of viral proteins from the nucleus of the host cell to the cytoplasm as well as an amplifier of the activities of pro-inflammatory transcription factors.
T300	38089-38193	Sentence	denotes	Thus, the CRM1 inhibitor selinexor may exert relevant antiviral and anti-inflammatory effects [122,123].
T301	38194-38362	Sentence	denotes	In fact, CRM1 inhibitors have exhibited activity against >20 different viruses, including RNA viruses such as respiratory syncytial virus and influenza virus [122,123].
T302	38363-38490	Sentence	denotes	Furthermore, CRM1 inhibition has also been identified in in vitro assays to have a potential activity against SARS-CoV-2 [124].
T303	38491-38611	Sentence	denotes	CRM1 was found to contribute to exporting several SARS-CoV proteins, such as S, N, 9b, Orf3 and Orf6 out of the nucleus.
T304	38612-38698	Sentence	denotes	Thus, CRM1 inhibition is expected to inhibit the viral assembly [125,126,127,128,129].
T305	38699-38880	Sentence	denotes	Moreover, CRM1 has also been found to contribute to the nuclear export and functional inactivation of antioxidant, anti-inflammatory, and cytoprotective transcription factors [130].
T306	38881-39023	Sentence	denotes	High levels of CRM1 are found in multiple inflammatory conditions and may magnify inflammatory responses leading to severe organ damage [131].
T307	39024-39234	Sentence	denotes	In this direction, selinexor and similar inhibitors have exhibited potent anti-inflammatory activity by suppressing the activation of NFkB and p38 signaling, leading to reduced cytokines in a variety of models.
T308	39235-39342	Sentence	denotes	For example, in a mouse model of sepsis, selinexor increased survival following a lethal dose of endotoxin.
T309	39343-39528	Sentence	denotes	Selinexor reduced the inflammatory cytokine secretion of IL-6, TNF-α, and HMGB1 while reducing the numbers of macrophage and polymorphonuclear neutrophils in the mice peritoneal cavity.
T310	39529-39654	Sentence	denotes	Selinexor also mitigated lipopolysaccharide-induced lung injury that is similar to acute respiratory distress syndrome [132].
T311	39655-39770	Sentence	denotes	Currently, selinexor is being evaluated in at least two phase 2 randomized trials in the U.S. in COVID-19 patients.
T312	39771-40203	Sentence	denotes	One is to evaluate the activity, safety and reduction in mortality of two regimens of low-dose selinexor in patients with moderate or severe COVID-19 (NCT04355676, n = 80) and the other is to evaluate the activity of low-dose selinexor and its effect on the clinical recovery, viral load, length of hospitalization, and rate of morbidity and mortality in participants with severe COVID-19 compared to placebo (NCT04349098, n = 230).
T313	40205-40209	Sentence	denotes	4.2.
T314	40210-40231	Sentence	denotes	Nitazoxanide (Alinia)
T315	40232-40336	Sentence	denotes	It is a nitro-thiazolyl-salicylamide derivative (Figure 7) with a broad-spectrum antimicrobial activity.
T316	40337-40430	Sentence	denotes	The drug is effective against various helminthic, protozoal, bacterial, and viral infections.
T317	40431-40458	Sentence	denotes	It was approved by the U.S.
T318	40459-40581	Sentence	denotes	FDA in 2002 to be used orally for the treatment of diarrhea caused by Cryptosporidium parvum or Giardia lamblia [133,134].
T319	40582-40675	Sentence	denotes	It is also off-label used for cryptosporidiosis-associated diarrhea in HIV-infected patients.
T320	40676-40800	Sentence	denotes	The drug has been reported as a broad-spectrum antiviral agent that inhibits the replication of several RNA and DNA viruses.
T321	40801-40943	Sentence	denotes	Specifically, nitazoxanide has been found to affect influenza A and B viruses as well as neuraminidase inhibitors-resistant influenza viruses.
T322	40944-41180	Sentence	denotes	It has also been found to inhibit the replication of coronavirus, dengue virus, HBV, HCV, HIV, Japanese encephalitis virus, norovirus, parainfluenza, rotavirus, respiratory syncytial virus, and yellow fever in cell culture assays [135].
T323	41181-41301	Sentence	denotes	Some of its activity is also potentially attributed to its active metabolite (tizoxanide), desacetyl-nitazoxanide [136].
T324	41302-41561	Sentence	denotes	Currently, nitazoxanide is being studied alone or in combination with hydroxychloroquine, ivermectin, ribavirin/ivermectin, or atazanavir/ritonavir for the prevention/treatment of COVID-19 in about 17 clinical trials (for details refer to clinicaltrials.gov).
T325	41562-41609	Sentence	denotes	The drug is associated with several mechanisms.
T326	41610-41782	Sentence	denotes	The anti-protozoal activity demonstrated by this drug is promoted by the inhibition of pyruvate:ferredoxin oxidoreductase enzyme-dependent electron transfer reaction [137].
T327	41783-42001	Sentence	denotes	However, in the case of influenza, nitazoxanide and its metabolite inhibit the viral hemagglutinin maturation at the post-translational phase with no effect on the M2 protein or on the neuraminidase glycoprotein [138].
T328	42002-42277	Sentence	denotes	Furthermore, nitazoxanide modulates other targets and pathways in vitro including glutamate-gated chloride ion channels and glutathione-S-transferase in nematodes, respiration and other pathways in bacterial and cancer cells, and viral and host transcriptional factors [134].
T329	42278-42444	Sentence	denotes	In fact, nitazoxanide was shown to in vitro inhibit the replication of coronaviruses, including MERS-CoV in cells and the expression of the viral N protein [136,139].
T330	42445-42589	Sentence	denotes	The drug was also reported as a non-competitive inhibitor of thiol oxidoreductase ERp57 and thus demonstrated anti-paramyxovirus activity [140].
T331	42590-42744	Sentence	denotes	Moreover, nitazoxanide was reported to inhibit the production of pro-inflammatory cytokines in peripheral blood mononuclear cells and animal models [136].
T332	42745-42888	Sentence	denotes	In peripheral blood mononuclear cells exposed to influenza virus, nitazoxanide potentiated the release of INF-α and INF-β by fibroblasts [135].
T333	42889-43038	Sentence	denotes	In addition, nitazoxanide appears also to act as a bronchodilator in testing models by blocking the calcium-activated chloride channel TMEM16A [141].
T334	43040-43044	Sentence	denotes	4.3.
T335	43045-43052	Sentence	denotes	NSAIDs:
T336	43053-43096	Sentence	denotes	Indomethacin (Indocin) and Naproxen (Aleve)
T337	43097-43210	Sentence	denotes	In one hand, indomethacin is a synthetic, small molecule of N-benzoyl-indole-3-acetic acid derivative (Figure 7).
T338	43211-43244	Sentence	denotes	It was first approved by the U.S.
T339	43245-43274	Sentence	denotes	FDA in 1984 for use as NSAID.
T340	43275-43330	Sentence	denotes	It also possesses analgesic and antipyretic properties.
T341	43331-43374	Sentence	denotes	It is used for acute mild to moderate pain.
T342	43375-43506	Sentence	denotes	It is also used for ankylosing spondylitis, bursitis, tendonitis, osteoarthritis, and rheumatoid arthritis, among other conditions.
T343	43507-43660	Sentence	denotes	The known mechanism is the reversible inhibition of cyclooxygenase-1 and 2 enzymes, which leads to decreased formation of prostaglandin precursors [142].
T344	43661-43912	Sentence	denotes	Orally administered indomethacin is being evaluated in combination with hydroxychloroquine and azithromycin in an open-label, single-arm, phase 2 study to determine its efficacy and safety in subjects with mild COVID-19 symptoms (NCT04344457; n = 80).
T345	43913-44224	Sentence	denotes	Considering activity against coronaviruses, in vitro studies demonstrated that indomethacin has a potent direct antiviral activity against the SARS coronavirus as determined in monkey Vero E6 cells and human lung epithelial A549 cells as well as against the canine coronavirus as determined in A72 canine cells.
T346	44225-44324	Sentence	denotes	Indomethacin blocked the viral RNA synthesis, but not the viral adhesion/entry into the host cells.
T347	44325-44385	Sentence	denotes	This effect is independent of the cyclooxygenase inhibition.
T348	44386-44522	Sentence	denotes	At a dose rate of 1 mg/kg, indomethacin resulted in more than 1000-fold reduction in the virus yield in coronavirus-infected dogs [143].
T349	44523-44752	Sentence	denotes	Likewise, indomethacin has been reported to be a potent inhibitor of SARS CoV-2 replication in Vero E6 cells with an IC50 value of 1 µM, which is 10-fold less than its peak plasma concentration, and a selective index of 500-fold.
T350	44753-45011	Sentence	denotes	Using a dose of 1 mg/kg in canine coronavirus-infected dogs, indomethacin accelerated the symptoms relieve and saved all infected animals, relative to ribavirin or anti-canine coronavirus serum/canine hemoglobin/canine blood immunoglobulin/INF regimen [144].
T351	45012-45147	Sentence	denotes	Previously, indomethacin also showed antiviral activity against rotavirus infection and vesicular stomatitis virus infection [145,146].
T352	45148-45338	Sentence	denotes	The antiviral activity of indomethacin was proposed to be a result of its binding to peroxisome proliferator activated receptor-γ, aldose reductase, and/or the viral NSP7/NSP8 complex [144].
T353	45339-45541	Sentence	denotes	The inhibition of the NSP7/NSP8 complex has been relatively verified and happened by indomethacin potentially targeting the interface between the host prostaglandin E synthase 2 and the viral NSP7/NSP8.
T354	45542-45663	Sentence	denotes	In fact, prostaglandin E synthase 2 itself is inhibited by indomethacin in Vero cells with an IC50 value of 750 nM [144].
T355	45664-45876	Sentence	denotes	Lastly, in addition to the inhibition of the pro-inflammatory prostaglandin biosynthesis, indomethacin was also found to halt the increase in IL-6 expression caused by lipopolysaccharide-treated U937 cells [147].
T356	45877-46005	Sentence	denotes	Accordingly, the effect of indomethacin on IL-6 may translate into beneficial effect in treating the cytokine storm of COVID-19.
T357	46006-46138	Sentence	denotes	In the other hand, naproxen is another synthetic, small molecule NSAID that is a derivative of 2-naphthalene-acetic acid (Figure 7).
T358	46139-46172	Sentence	denotes	It was first approved by the U.S.
T359	46173-46435	Sentence	denotes	FDA in 1976 for oral use in the treatment of a host of painful inflammatory conditions such as ankylosing spondylitis, bursitis, polyarticular juvenile idiopathic arthritis, osteoarthritis, rheumatoid arthritis, tendonitis, dysmenorrhea pain, and gout [148,149].
T360	46436-46613	Sentence	denotes	The efficacy of naproxen in the treatment of critically ill, hospitalized COVID-19 patients is being evaluated in a randomized, open label clinical trial (NCT04325633; n = 584).
T361	46614-46750	Sentence	denotes	The drug has been reported to exhibit antiviral activity against influenza A and B viruses with IC50 values in the low micromolar range.
T362	46751-46857	Sentence	denotes	In this arena, naproxen antagonized CRM1-mediated nuclear export of proteins of influenza A and B viruses.
T363	46858-46954	Sentence	denotes	Naproxen also provided therapeutic protection to mice infected with influenza B virus [150,151].
T364	46955-47109	Sentence	denotes	In hospitalized patients with influenza, it was found that adding clarithromycin and naproxen to oseltamivir shortened the hospitalization time [150,151].
T365	47110-47238	Sentence	denotes	Naproxen also inhibited the replication of Zika virus by reducing the expression of AXL, the entry cofactor of Zika virus [152].
T366	47239-47420	Sentence	denotes	Naproxen’s antiviral activity against SARS-CoV-2 has also been proposed by a recent computational work and has been attributed its ability to bind to the viral nucleocapsid protein.
T367	47421-47626	Sentence	denotes	In fact, it was recently reported that naproxen inhibits SARS-CoV-2 infection in Vero E6 cells and in reconstituted human airway epithelia with IC50 values comparable to those effective in influenza [153].
T368	47627-47788	Sentence	denotes	Lastly, similar to indomethacin, the anti-inflammatory effects of naproxen may also translate into beneficial effects in treating the cytokine storm of COVID-19.
T369	47790-47794	Sentence	denotes	4.4.
T370	47795-47861	Sentence	denotes	Vidofludimus Calcium (Immunic AG, IMU-838) and Brequinar (DuP-785)
T371	47862-48055	Sentence	denotes	Vidofludimus is a synthetic small molecule that is under investigation for treating inflammatory bowel disease, multiple sclerosis, and other inflammatory and autoimmune diseases [154,155,156].
T372	48056-48182	Sentence	denotes	It is a biphenyl-carbamoyl-cyclopentene derivative (Figure 7) that is being developed as oral formulation for therapeutic use.
T373	48183-48415	Sentence	denotes	Currently, a prospective, randomized, multi-center, double-blinded, and placebo-controlled study is ongoing to evaluate the safety and efficacy of vidofludimus as an adjunct therapy in COVID-19 patients (NCT04379271; n = 230) [157].
T374	48416-48608	Sentence	denotes	The investigational drug selectively inhibits dihydroorotate dehydrogenase, an important enzyme for the de novo biosynthesis of pyrimidine-based nucleotides, in activated B and T immune cells.
T375	48609-48729	Sentence	denotes	Such inhibition diminishes the pyrimidine pool in these cells, which subsequently exposes the cells to metabolic stress.
T376	48730-48883	Sentence	denotes	It also diminishes the release of T helper 1 (Th1) and T helper 17 (Th17) proinflammatory cytokines of IL-17 and IFN-γ, which reduces inflammation [154].
T377	48884-49102	Sentence	denotes	Interestingly, dihydroorotate dehydrogenase inhibition also results in a direct antiviral effect, which has been exhibited in cells infected with hemorrhagic fever-causing viruses, cytomegalovirus, and influenza virus.
T378	49103-49247	Sentence	denotes	In fact, IMU-838′s antiviral activity has been demonstrated in vitro against arenavirus, cytomegalovirus, influenza A virus, HCV, and HIV [157].
T379	49248-49330	Sentence	denotes	IMU-838 has also effectively promoted antiviral activity against SARS-CoV-2 [157].
T380	49331-49414	Sentence	denotes	Specifically, IMU-838 inhibited the replication of clinical isolates of SARS-CoV-2.
T381	49415-49600	Sentence	denotes	In cellular assays, IMU-838 promoted the anti-SARS-CoV-2 activity at concentrations lower than those that have been considered in previous and ongoing clinical trials [154,155,156,157].
T382	49601-49888	Sentence	denotes	Overall, IMU-838′s antiviral activity against SARS-CoV-2 as well as its selective immunomodulatory effect targeting activated immune cells appear to be interesting, particularly that it potentially prevents the virus reactivation that may happen with other immunomodulatory agents [157].
T383	49889-50041	Sentence	denotes	Likewise, brequinar is a synthetic, small molecule, and quinoline-carboxylic acid derivative (Figure 7) that also inhibits dihydroorotate dehydrogenase.
T384	50042-50130	Sentence	denotes	It eventually blocks the de novo biosynthesis of pyrimidine-based nucleotides [158,159].
T385	50131-50190	Sentence	denotes	Accordingly, brequinar possesses immunosuppressive effects.
T386	50191-50349	Sentence	denotes	Furthermore, it also possesses antineoplastic properties that can be exploited to enhance the in vivo antitumor activity of other antineoplastic agents [160].
T387	50350-50415	Sentence	denotes	Alternatively, the drug has also antiparasitic effects [160,161].
T388	50416-50573	Sentence	denotes	More importantly, the drug exhibits a broad-spectrum antiviral activity against influenza viruses [162], HIV-1 [163], and foot-and-mouth disease virus [164].
T389	50574-50727	Sentence	denotes	In fact, a pre-print under review has documented the activity of dihydroorotate dehydrogenase inhibitors against RNA viruses, including SARS-CoV-2 [165].
T390	50728-50911	Sentence	denotes	Currently, the drug is being evaluated in a randomized, open-label trial to assess its safety and anti-coronavirus activity in hospitalized adults with COVID-19 (NCT04425252; n = 24).
T391	50913-50917	Sentence	denotes	4.5.
T392	50918-50937	Sentence	denotes	Famotidine (Pepcid)
T393	50938-51053	Sentence	denotes	Famotidine is a synthetic guandino-thiazole derivative (Figure 7) that acts as a potent and competitive H2-blocker.
T394	51054-51087	Sentence	denotes	It was first approved by the U.S.
T395	51088-51141	Sentence	denotes	FDA in 1986 and now is used as over-the-counter drug.
T396	51142-51256	Sentence	denotes	It can be used orally or parenterally to treat gastroesophageal reflux disease, heartburn, and peptic ulcer [166].
T397	51257-51526	Sentence	denotes	Recently, a retrospective non-randomized study by Columbia University, Northwell Health, and Massachusetts General Hospital showed that famotidine, and not proton pump inhibitors, reduced the risk of intubation or death in hospitalized COVID-19 patients (n = 84) [167].
T398	51527-51818	Sentence	denotes	Furthermore, a case series indicated that COVID-19 patients (n = 10) who frequently self-administered a high-dose of oral famotidine (most frequent dose was 80 mg three times/day for a median of 11 days) reported significant symptoms improvement within 24 hours of starting famotidine [168].
T399	51819-52161	Sentence	denotes	Therefore, intravenously administered famotidine with standard of care (orally administered hydroxychloroquine and has progressed to include remdesivir) is currently being studied in a multi-site, randomized, double-blind, multi-arm historical control, comparative trial that is sponsored by Northwell Health, New York (NCT04370262; n = 942).
T400	52162-52353	Sentence	denotes	Famotidine has been identified via virtual screening and molecular modeling, docking, and scoring as a potential inhibitor of Mpro [169], yet this potential is to be experimentally confirmed.
T401	52355-52359	Sentence	denotes	4.6.
T402	52360-52368	Sentence	denotes	VERU-111
T403	52369-52542	Sentence	denotes	It is an orally bioavailable, 3-substituted indole derivative (Figure 8A) and microtubule depolymerization agent that recognizes colchicine-binding site on tubulin subunits.
T404	52543-52599	Sentence	denotes	It has been under clinical development for cancer [170].
T405	52600-52811	Sentence	denotes	Drugs targeting microtubules have broad antiviral activity because they disrupt the intracellular transport of viruses, including SARS CoV-2, along microtubules, which is critical for viruses to cause infection.
T406	52812-52985	Sentence	denotes	Microtubule depolymerization agents also have strong anti-inflammatory effects that can be beneficial in mitigating the cytokine storm induced by SARS-CoV-2 infection [171].
T407	52986-53196	Sentence	denotes	The drug is currently being evaluated in a phase 2 randomized, placebo-controlled study for the treatment of SARS-CoV-2 in patients at elevated risk of acute respiratory distress syndrome (NCT04388826; n = 40).
T408	53197-53309	Sentence	denotes	Of note, it is mechanistically similar to colchicine, which has also been considered in COVID-19 patients [172].
T409	53311-53315	Sentence	denotes	4.7.
T410	53316-53335	Sentence	denotes	Leflunomide (Arava)
T411	53336-53422	Sentence	denotes	It is a synthetic, small molecule and an isoxazole-carboxamide derivative (Figure 8B).
T412	53423-53450	Sentence	denotes	It was approved by the U.S.
T413	53451-53524	Sentence	denotes	FDA in 1998 for the oral treatment of rheumatoid arthritis [173,174,175].
T414	53525-53731	Sentence	denotes	It is also used off-label as a replacement therapy in kidney transplant recipients with polyomavirus BK [176] and for cytomegalovirus disease in transplant recipients resistant to standard antivirals [177].
T415	53732-53834	Sentence	denotes	Mechanistically, it is a disease-modifying agent with anti-inflammatory and antiproliferative effects.
T416	53835-54013	Sentence	denotes	It inhibits pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, an important enzyme in the de novo synthesis of uridine monophosphate [178].
T417	54014-54153	Sentence	denotes	Leflunomide is a prodrug and the active metabolite (isoxazole ring is open: teriflunomide (Aubagio)) is responsible for its activity [179].
T418	54154-54215	Sentence	denotes	It inhibits rapidly dividing cells such as activated T cells.
T419	54216-54279	Sentence	denotes	It has also been found to block the transcription factor NF-κB.
T420	54280-54321	Sentence	denotes	It also inhibits tyrosine kinase enzymes.
T421	54322-54493	Sentence	denotes	The drug inhibits the replication of cytomegalovirus, herpes simplex virus 1, and polyomavirus BK by interfering with nucleocapsid tegumentation and virion assembly [179].
T422	54494-54688	Sentence	denotes	Given the above activities, a high dose of leflunomide is being evaluated for the treatment of ambulatory patients with mild COVID-19 at the University of Chicago Medicine (NCT04361214; n = 20).
T423	54690-54694	Sentence	denotes	4.8.
T424	54695-54715	Sentence	denotes	Sirolimus (Rapamune)
T425	54716-54802	Sentence	denotes	Sirolimus is a natural macrolide (Figure S5) obtained from Streptomyces hygroscopicus.
T426	54803-54836	Sentence	denotes	It was first approved by the U.S.
T427	54837-54923	Sentence	denotes	FDA in 1999 and is orally used for lymphangioleiomyomatosis and renal transplantation.
T428	54924-55041	Sentence	denotes	Mechanistically, the drug is an immunosuppressive agent and an inhibitor of the mammalian target of rapamycin (mTOR).
T429	55042-55182	Sentence	denotes	Sirolimus forms an immunosuppressive complex with FK-binding protein-12, and subsequently, the complex inhibits the regulatory kinase, mTOR.
T430	55183-55304	Sentence	denotes	This inhibition suppresses cytokine mediated proliferation of T and B cells as well as the antibody production [180,181].
T431	55305-55461	Sentence	denotes	Furthermore, the drug may influence the virus because mTOR complex 1 is involved in the replication of various viruses, including coronavirus [182,183,184].
T432	55462-55582	Sentence	denotes	Furthermore, in vitro studies demonstrated a specific inhibitory activity against MERS-CoV infection by sirolimus [184].
T433	55583-55836	Sentence	denotes	In an open-label, prospective randomized study in H1N1 pneumonia patients, treatment with sirolimus and corticosteroids combination for two weeks alleviated hypoxia, shortened the mechanical ventilation duration, and improved multi-organ function [185].
T434	55837-55997	Sentence	denotes	Accordingly, sirolimus is being tested for the treatment of COVID-19 patients either alone or in combination with hydroxychloroquine in several clinical trials.
T435	55998-56158	Sentence	denotes	Likewise, RTB101 (dactolisib), another mTOR inhibitor and phosphoinositide 3-kinase inhibitor, is also being tested in COVID-19 patients (NCT04409327; n = 550).
T436	56160-56164	Sentence	denotes	4.9.
T437	56165-56186	Sentence	denotes	Plitidepsin (Aplidin)
T438	56187-56290	Sentence	denotes	It is a cyclic depsipeptide natural product (Figure S5) that is extracted from Aplidium albicans [186].
T439	56291-56425	Sentence	denotes	It is used for acute lymphoblastic leukemia and, with dexamethasone, for patients with refractory and relapsed multiple myeloma [187].
T440	56426-56538	Sentence	denotes	Recently, the molecule was reported to have in vitro nanomolar potency against the human coronavirus 229E [188].
T441	56539-56789	Sentence	denotes	The mechanism is thought to be similar to its anticancer activity, i.e., targeting eukaryotic translation elongation factor 1-α1, which has been reported to play an unexpected role in the replication and pathogenesis of various RNA viruses [189,190].
T442	56790-56880	Sentence	denotes	The drug is being tested in phase 1 trial in patients with COVID-19 (NCT04382066; n = 27).
T443	56882-56887	Sentence	denotes	4.10.
T444	56888-56912	Sentence	denotes	Cyclosporine A (Gengraf)
T445	56913-57013	Sentence	denotes	Cyclosporine A is a cyclic peptide that is naturally obtained from the fungus Beauveria nivea [191].
T446	57014-57102	Sentence	denotes	It is immunosuppressant and calcineurin inhibitor that inhibits T cell activation [192].
T447	57103-57201	Sentence	denotes	It binds to the intracellular receptor cyclophilin-1 producing a cyclosporine-cyclophilin complex.
T448	57202-57372	Sentence	denotes	This complex subsequently inhibits calcineurin, which stops the activation of the nuclear factor of activated T cells (NF-AT) that normally causes inflammatory reactions.
T449	57373-57506	Sentence	denotes	The inhibition of NF-AT also leads to lower levels of other factors associated with T helper cell function and thymocyte development.
T450	57507-57550	Sentence	denotes	Cyclosporine was first approved by the U.S.
T451	57551-57819	Sentence	denotes	FDA in 1983 and is orally, parenterally, or topically used to prevent organ transplant rejection, treat/prevent graft-versus-host disease, and treat various inflammatory and autoimmune conditions such as severe rheumatoid arthritis and psoriasis [191,192,193,194,195].
T452	57820-58007	Sentence	denotes	Importantly, low micromolar concentrations of cyclosporin A (<35 µM) substantially impacted the replication of SARS-CoV, human coronavirus 229E, and mouse hepatitis virus in cell culture.
T453	58008-58089	Sentence	denotes	Cyclosporin A significantly inhibited gene expression and reduced progeny titers.
T454	58090-58174	Sentence	denotes	Cyclosporin A treatment completely blocked SARS-CoV RNA and protein synthesis [196].
T455	58175-58346	Sentence	denotes	Cyclosporine A also in vitro reduced the replication of MERS-CoV, transmissible gastroenteritis coronavirus, porcine epidemic diarrhea virus, and feline coronavirus [196].
T456	58347-58421	Sentence	denotes	In fact, cyclosporine A has demonstrated broad-spectrum antiviral effects.
T457	58422-58478	Sentence	denotes	It inhibited the replication of HBV, HCV, and HIV [197].
T458	58479-58724	Sentence	denotes	Cyclosporine also inhibited the replication of Zika virus, West Nile virus, Rift Valley fever virus, and influenza A virus by blocking the interaction of cellular cyclophilins with viral proteins as well as by inhibiting the RNA synthesis [198].
T459	58725-58802	Sentence	denotes	By targeting cyclophilins, the drug can also prevent acute lung injury [199].
T460	58803-59084	Sentence	denotes	Currently, the use of cyclosporin A is being tested in patients with moderate COVID-19 (NCT04412785; n = 20), hospitalized COVID-19 patients (NCT04392531; n = 120), and combined with topical corticosteroid in COVID-19 patients with acute keratoconjunctivitis (NCT04451239; n = 12).
T461	59085-59144	Sentence	denotes	It has also been used in psoriatic COVID-19 patients [200].
T462	59146-59151	Sentence	denotes	4.11.
T463	59152-59175	Sentence	denotes	Deferoxamine (Desferal)
T464	59176-59256	Sentence	denotes	Deferoxamine (Figure S5) is a natural chelating agent from Streptomyces pilosus.
T465	59257-59290	Sentence	denotes	It was first approved by the U.S.
T466	59291-59357	Sentence	denotes	FDA in 1968 and has been parenterally used to treat iron toxicity.
T467	59358-59513	Sentence	denotes	The drug complexes with the ferric ion, primarily in the vascular space, to form ferrioxamine complex that gets subsequently eliminated in urine [201,202].
T468	59514-59595	Sentence	denotes	There are reports about unusually high serum ferritin in COVID-19 patients [203].
T469	59596-59746	Sentence	denotes	A retrospective, multicenter cohort study reported increased levels of serum ferritin in COVID-19 non-survivors compared with COVID-19 survivors [99].
T470	59747-59875	Sentence	denotes	The increase in serum ferritin indicates dysregulated iron homeostasis pertaining to oxidative stress and inflammatory response.
T471	59876-60066	Sentence	denotes	Dysregulated iron homeostasis may propagate the viral infections leading to severe respiratory illnesses such as pulmonary fibrosis and acute respiratory distress syndrome [204,205,206,207].
T472	60067-60188	Sentence	denotes	Accordingly, the use of iron chelators, particularly deferoxamine, in managing/treating COVID-19 has been proposed [208].
T473	60189-60403	Sentence	denotes	Deferoxamine may exert an antiviral effect by depleting iron availability, which has been shown to play a critical role in the replication of RNA viruses such as HCV, HIV, and West Nile virus [209,210,211,212,213].
T474	60404-60510	Sentence	denotes	In addition to its effect on iron level, deferoxamine also appears to have immunomodulatory effects [209].
T475	60511-60628	Sentence	denotes	Along these lines, deferoxamine mitigated the symptoms of Enterovirus-infected mice and decreased the mortality rate.
T476	60629-60718	Sentence	denotes	It also upregulated the B cell levels and improved the neutralizing antibody titer [209].
T477	60719-60866	Sentence	denotes	Deferoxamine has also been reported to in vitro block endothelial inflammation induced by influenza A infection by inhibiting IL-6 synthesis [214].
T478	60867-60915	Sentence	denotes	Deferoxamine may also have antifibrotic effects.
T479	60916-61093	Sentence	denotes	An intranasal treatment with deferoxamine was reported to prevent pulmonary fibrosis and pulmonary functional decline in bleomycin-induced pulmonary fibrosis animal model [206].
T480	61095-61100	Sentence	denotes	4.12.
T481	61101-61120	Sentence	denotes	Atovaquone (Mepron)
T482	61121-61237	Sentence	denotes	Atovaquone is an orally active, synthetic hydroxy-naphthoquinone derivative (Figure S6) with antiparasitic activity.
T483	61238-61265	Sentence	denotes	It was approved by the U.S.
T484	61266-61325	Sentence	denotes	FDA in 1992 against Pneumocystis jirovecii pneumonia [215].
T485	61326-61429	Sentence	denotes	It has also been used to prevent and/or treat toxoplasmosis, malaria, and babesiosis [216,217,218,219].
T486	61430-61620	Sentence	denotes	Mechanistically, it inhibits the electron transport chain in mitochondria, leading to the inhibition of critical metabolic enzymes important for the synthesis of nucleic acids and ATP [220].
T487	61621-61850	Sentence	denotes	It is being evaluated in the U.S. alone (NCT04456153; n = 60) or in combination with azithromycin in an open-label, non-randomized study in COVID-19 patients at HonorHealth Clinical Research Institute, U.S. (NCT04339426; n = 25).
T488	61851-61957	Sentence	denotes	One potential mechanism of action for atovaquone pertaining to SARS-CoV-2 is the inhibition of Mpro [221].
T489	61958-62027	Sentence	denotes	Another computational study suggested that it may inhibit RdRp [169].
T490	62028-62108	Sentence	denotes	Importantly, these computational studies are yet to be experimentally confirmed.
T491	62110-62115	Sentence	denotes	4.13.
T492	62116-62126	Sentence	denotes	Levamisole
T493	62127-62240	Sentence	denotes	It is a tetrahydro-imidazothiazole derivative (Figure S6) that has been used for its immunomodulatory properties.
T494	62241-62284	Sentence	denotes	It was first introduced by Janssen in 1969.
T495	62285-62393	Sentence	denotes	Ever since, it was used as a disease-modifying drug for the treatment of rheumatoid arthritis [222,223,224].
T496	62394-62464	Sentence	denotes	It was also used with 5-fluorouracil for colon cancer treatment [225].
T497	62465-62655	Sentence	denotes	Currently, it is primarily used as an anthelmintic agent for the treatment of ascariasis and hookworm infections owing to its effect on the parasitic nicotinic acetylcholine receptors [226].
T498	62656-62782	Sentence	denotes	It is also used by pediatric nephrologists as a steroid-sparing agent in childhood steroid-dependent nephrotic syndrome [227].
T499	62783-63061	Sentence	denotes	A recent computational exercise has suggested that levamisole potentially binds to the catalytic domain of the viral PLpro, a viral enzyme that processes the newly biosynthesized viral polyproteins and eventually contributes to the maturation and infectivity of the virus [228].
T500	63062-63121	Sentence	denotes	Yet, no experimental validation has been reported thus far.
T501	63122-63293	Sentence	denotes	As of now, orally administered levamisole is being studied alone or in combination with budesonide/formoterol inhaler for the treatment of COVID-19 in few clinical trials.
T502	63294-63370	Sentence	denotes	The rationale for this use has been because of its immunomodulatory effects.
T503	63371-63497	Sentence	denotes	Levamisole acts as an immune-modulator and immune-enhancer by increasing T-cell lymphocyte function and macrophage chemotaxis.
T504	63498-63638	Sentence	denotes	It has also been shown to up-regulate toll-like receptors, stimulate neutrophil chemotaxis, and enhance dendritic cell maturation [229,230].
T505	63639-63749	Sentence	denotes	Furthermore, levamisole attenuated alveolar macrophage dysfunction in respiratory virus-infected calves [231].
T506	63751-63756	Sentence	denotes	4.14.
T507	63757-63765	Sentence	denotes	BLD-2660
T508	63766-63914	Sentence	denotes	It an orally bioavailable, small molecule, reversible covalent inhibitor of calpains, non-lysosomal cysteine proteases, with anti-fibrotic activity.
T509	63915-64086	Sentence	denotes	BLD-2660 exhibited potent and selective inhibition of calpains 1,2, and 9 and thus was found to be efficacious in multiple animal fibrosis models of skin, liver, and lung.
T510	64087-64152	Sentence	denotes	It exhibited high selectivity against related cysteine proteases.
T511	64153-64256	Sentence	denotes	Earlier, several calpain inhibitors were found to reduce the viral replication of SARS-CoV-1 [232,233].
T512	64257-64428	Sentence	denotes	The antiviral activity by calpain inhibition was also verified using siRNA to selectively silence expression of the calpain 2 isoform in SARS-CoV infected cells [232,233].
T513	64429-64548	Sentence	denotes	Undisclosed inhibitors by the developing company were found to reduce SARS-CoV-2 replication in Vero cell-based assays.
T514	64549-64729	Sentence	denotes	Furthermore, in preclinical animal models of lung injury and fibrosis, BLD-2660 was shown to reduce the expression/production of IL-6 in injured lungs and to reduce fibrosis [234].
T515	64730-64988	Sentence	denotes	Owing to the antiviral and anti-inflammatory activities of BLD-2660, it has been advanced to a phase 2, randomized, double-blind, placebo-controlled study to evaluate its safety and antiviral activity in COVID-19 hospitalized subjects (NCT04334460; n = 120).

T16

0-2

Sentence

denotes

1.

T17

3-15

Sentence

denotes

Introduction

T18

16-298

Sentence

denotes

Over the last 20 years, humanity has dealt with three serious coronavirus infection outbreaks, namely severe acute respiratory syndrome coronavirus (SARS-CoV, 2002–2003) [1], Middle East respiratory syndrome coronavirus (MERS-CoV, 2012–2019) [2], and SARS-CoV-2, (2019-present) [3].

T19

299-559

Sentence

denotes

Although it appears that the fatality rates for the first two outbreaks are much higher (9.2% and 37%, respectively) than the ongoing pandemic (~3.3% as of 5 September 2020) [4,5], the ongoing infectious disease of SARS-CoV-2 appears to be far more contagious.

T20

560-728

Sentence

denotes

The ongoing outbreak, widely known as coronavirus disease of 2019 (COVID-19), was recognized by the World Health Organization as a global pandemic on 11 March 2020 [6].

T21

729-864

Sentence

denotes

As of 5 September 2020, there have been more than 26.7 million confirmed cases worldwide with more than 876 thousand global deaths [4].

T22

865-960

Sentence

denotes

Efforts are ongoing to deliver an effective vaccine to protect individuals against the disease.

T23

961-1111

Sentence

denotes

Likewise, potential therapeutics to prevent and/or treat the disease and its complications are being advanced to clinical trials all around the world.

T24

1112-1531

Sentence

denotes

In this direction, effective treatments for COVID-19 patients, particularly those who have the severe version of the disease and become critically ill needing hospitalization, intensive care unit (ICU) admission, and mechanical ventilation, appear to include antiviral drugs as well as anti-inflammatory drugs and anticoagulant drugs to also treat the associated cytokine storm [7] and coagulopathies [8], respectively.

T25

1532-1688

Sentence

denotes

Considering the current clinical guidelines, remdesivir has been recommended for the treatment of COVID-19 in hospitalized patients with severe disease [9].

T26

1689-1809

Sentence

denotes

Furthermore, favipiravir has been approved for the treatment of COVID-19 in the hospital settings in few countries [10].

T27

1810-1978

Sentence

denotes

Moreover, dexamethasone as an anti-inflammatory drug has also been recommended in patients with COVID-19 who require mechanical ventilation or supplemental oxygen [11].

T28

1979-2086

Sentence

denotes

Despite the above recommendations and/or approvals, the need for effective treatment remains largely unmet.

T29

2087-2215

Sentence

denotes

Therefore, a large number of potential therapeutics continue to be developed and others are being advanced into clinical trials.

T30

2216-2349

Sentence

denotes

We recently reviewed the chemical and mechanistic aspects of antiviral drugs that block the early phase of the virus life cycle [12].

T31

2350-2531

Sentence

denotes

In this article, we review the chemical structures and the mechanisms of action of potential antiviral therapeutics that block/inhibit the post-entry stages of the virus life cycle.

T32

2532-2604

Sentence

denotes

We only include those therapeutics that are listed in clinicatrials.gov.

T33

2605-2660

Sentence

denotes

They include both old drugs and new molecular entities.

T34

2661-2743

Sentence

denotes

Many of the potential therapeutics are small molecules and few are macromolecules.

T35

2744-2810

Sentence

denotes

Some of these therapeutics also possess anti-inflammatory effects.

T36

2812-2883

Sentence

denotes

The Life Cycle of SARS-COV-2 and Potential Targets for Drug Development

T37

2884-2977

Sentence

denotes

The life cycle of the virus includes early-stage events and later-stage events (Figure 1a,b).

T38

2978-3123

Sentence

denotes

In the first stage, the virus utilizes its spike (S) protein to bind to angiotensin converting enzyme 2 (ACE2) on the host cell membrane [13,14].

T39

3124-3388

Sentence

denotes

The virus enters the host cell after the spike S protein-ACE2 complex is proteolytically activated by transmembrane protease serine 2 (TMPRSS2) (see (b) in Figure 1), which eventually permits the virus-host cell fusion and the release of the viral RNA genome [15].

T40

3389-3488

Sentence

denotes

Alternatively, the bound virus spike S protein can also be proteolytically activated by furin [16].

T41

3489-3687

Sentence

denotes

Further processing is promoted by cathepsins in (endo)lysosomes to ultimately aid in the viral envelope fusion with the host membranes and the release of the viral genome (see (a) in Figure 1) [17].

T42

3688-3908

Sentence

denotes

The RNA genome of SARS-CoV-2 has more than 29,800 nucleotides which encode for about 29 proteins: nonstructural proteins (NSPs; 16 proteins), structural proteins (4 proteins), and accessory proteins (9 proteins) [18,19].

T43

3909-4089

Sentence

denotes

The structural proteins are spike S protein, envelope (E) and membrane (M) proteins which form the viral envelope, and nucleocapsid (N) protein which binds to the virus RNA genome.

T44

4090-4408

Sentence

denotes

In the post-entry phase of the virus life cycle (Figure 1), the NSPs domain is expressed as two polypeptides which, after processing, produce papain like protease (PLpro) (NSP3), main protease (Mpro) (also known as 3-chymotrypsin-like protease (3CLpro); NSP5) [20], and RNA-dependent RNA polymerase (RdRp; NSP12) [21].

T45

4409-4549

Sentence

denotes

Initial processing of the two polypeptides is promoted by host proteases, and then, is propagated by the action of the viral PLpro and Mpro.

T46

4550-4643

Sentence

denotes

The viral RdRp is also responsible for the replication and amplification of the viral genome.

T47

4644-4894

Sentence

denotes

The viral RNA and the N structural protein are biosynthesized in the host cell cytoplasm, whereas other viral structural proteins including S, M, and E are eventually biosynthesized in the endoplasmic reticulum and transported to the Golgi apparatus.

T48

4895-5066

Sentence

denotes

The viral RNA–N complex and S, M, and E proteins are then assembled in the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) to produce a mature virus particle.

T49

5067-5216

Sentence

denotes

The mature virus is then released from the Golgi apparatus via a budding process and next from the host cells by exocytosis (Figure 1) [12,22,23,24].

T50

5217-5378

Sentence

denotes

Collectively, the goal of antiviral therapeutics is to inhibit one or more events in the life cycle of the virus in order to impede the propagation of infection.

T51

5379-5526

Sentence

denotes

Along these lines, any protein or event in the virus life cycle can be considered as a molecular target for anti-COVID-19 drug development efforts.

T52

5527-5695

Sentence

denotes

In this review, we describe the antiviral agents that are currently being tested in clinical trials to block and/or inhibit the advanced events of the virus life cycle.

T53

5696-5874

Sentence

denotes

Although the majority of the presented antiviral therapeutics target the viral polymerase or the viral proteases, few other therapeutics target other molecular targets (Table 1).

T54

5876-5878

Sentence

denotes

2.

T55

5879-5906

Sentence

denotes

Viral Polymerase Inhibitors

T56

5908-5912

Sentence

denotes

2.1.

T57

5913-5942

Sentence

denotes

Remdesivir (Veklury, GS-5734)

T58

5943-6045

Sentence

denotes

Remdesivir is an adenosine monophosphate derivative and nucleotide-based antiviral prodrug (Figure 2).

T59

6046-6124

Sentence

denotes

Remdesivir received, in May 2020, an emergency use authorization from the U.S.

T60

6125-6262

Sentence

denotes

FDA for the treatment of laboratory-confirmed or suspected COVID-19 illness in children and adults hospitalized with severe disease [25].

T61

6263-6390

Sentence

denotes

The parenterally administered drug is being developed by Gilead Sciences, U.S., and has broad-spectrum antiviral activity [26].

T62

6391-6466

Sentence

denotes

It was first studied in 2016 as a potential treatment for Ebola virus [27].

T63

6467-6635

Sentence

denotes

In addition to its activity against SARS-CoV-2, remdesivir has a potential to treat a variety of infections caused by RNA viruses, including SARS-CoV and MERS-CoV [28].

T64

6636-6773

Sentence

denotes

The drug is metabolized to the pharmacologically active nucleoside triphosphate metabolite after being distributed into cells (Figure 2).

T65

6774-6946

Sentence

denotes

The triphosphate metabolite acts as a competitive inhibitor of RdRp and thus eventually causes chain elongation termination, which decreases the viral RNA replication [29].

T66

6947-7043

Sentence

denotes

The termination is delayed and happens after the addition of more nucleotides (between 3 and 5).

T67

7044-7152

Sentence

denotes

Therefore, remdesivir is described as a direct antiviral agent acting as a delayed chain terminator [30,31].

T68

7153-7230

Sentence

denotes

Importantly, remdesivir avoids proofreading by viral exoribonuclease [28,32].

T69

7231-7346

Sentence

denotes

Currently, remdesivir is being evaluated as a treatment for COVID-19 patients in about 15 studies across the globe.

T70

7347-7528

Sentence

denotes

The drug is being tested alone or in combination with merimepodib (NCT04410354; n = 40), tocilizumab (NCT04409262; REMDACTA; n = 450), or baricitinib (NCT04401579; ACTT2; n = 1034).

T71

7529-7640

Sentence

denotes

In particular, merimepodib is another antiviral agent that is inhibitor of inosine monophosphate dehydrogenase.

T72

7641-7705

Sentence

denotes

The enzyme is required for the synthesis of guanine nucleotides.

T73

7706-7821

Sentence

denotes

Merimepodib consequently inhibits the synthesis of DNA and RNA, leading to antiviral and immunosuppressive effects.

T74

7822-7926

Sentence

denotes

Thus, remdesivir and merimepodib is a dual-acting antiviral combination with immunosuppressive activity.

T75

7927-8074

Sentence

denotes

Remdesivir itself demonstrated in vitro activity against Vero E6 cells infected with SARS-CoV-2 with an EC50 value of 0.77 µM (CC50 > 100 µM) [33].

T76

8075-8272

Sentence

denotes

Remdesivir also exhibited in vitro activity against SARS-CoV and MERS-CoV in multiple in vitro systems, including primary human airway epithelial cell cultures with sub-micromolar IC50 values [28].

T77

8273-8475

Sentence

denotes

Remdesivir was also effective against pre-pandemic bat-CoVs, bat-CoVs, and contemporary circulating human coronaviruses in primary human lung cells suggesting a broad-spectrum anti-coronavirus activity.

T78

8476-8704

Sentence

denotes

In a mouse model of SARS-CoV, the prophylactic and early therapeutic use of remdesivir significantly decreased the lung viral load and improved the respiratory functions as well as the overall clinical signs of the disease [28].

T79

8705-8844

Sentence

denotes

Furthermore, remdesivir with interferon (INF)-b demonstrated better antiviral activity compared to lopinavir/ritonavir with INF-b in vitro.

T80

8845-9061

Sentence

denotes

Compared to lopinavir/ritonavir/INF-b, the prophylactic and therapeutic use of remdesivir also more effectively diminished the pulmonary viral loads and improved the pulmonary function in mice model of MERS-CoV [34].

T81

9062-9206

Sentence

denotes

The efficacy of the prophylactic and therapeutic use of remdesivir was also demonstrated in the rhesus macaque model of MERS-CoV infection [35].

T82

9207-9364

Sentence

denotes

Very recently, remdesivir was also shown to inhibit SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM).

T83

9365-9562

Sentence

denotes

In mice infected with a chimeric SARS-CoV encoding RdRp, therapeutic administration of remdesivir diminished lung viral load and improved pulmonary function compared with vehicle-treated mice [36].

T84

9563-9916

Sentence

denotes

As far as clinical trials in humans, a randomized, placebo-controlled, double-blind trial in hospitalized adults (n = 236) with severe COVID-19 in China initially revealed that the median time to improvement was not substantially different in the remdesivir group (200 mg on the first day, and then 100 mg/day for 9 days) from that of the placebo group.

T85

9917-9976

Sentence

denotes

The mortality rate was also similar in the two groups [37].

T86

9977-10040

Sentence

denotes

Yet, the trial was criticized for being insufficiently powered.

T87

10041-10319

Sentence

denotes

Later, a phase 3 randomized, open-label trial in adults (n = 397) hospitalized with severe COVID-19 sponsored by Gilead revealed that the time to clinical improvement for 50% of patients was 10 days in the 5-day treatment group relative to 11 days in the 10-day treatment group.

T88

10320-10412

Sentence

denotes

The dose regimen used was 200 mg on day 1, followed by 100 mg/day for total of 5 or 10 days.

T89

10413-10544

Sentence

denotes

At day 14, about 64.5% of the patients in the 5-day group and 53.8% of the patients in the 10-day group achieved clinical recovery.

T90

10545-10703

Sentence

denotes

Patients treated with remdesivir within 10 days of symptoms onset achieved better outcomes relative to those treated after more than 10 days of symptoms [38].

T91

10704-10805

Sentence

denotes

Similar results were obtained in hospitalized adults (n = 1600) with moderate COVID-19 (NCT04292730).

T92

10806-10948

Sentence

denotes

In an uncontrolled study of hospitalized COVID-19 patients (n = 61), most patients needed less oxygen support after receiving remdesivir [39].

T93

10949-11040

Sentence

denotes

Importantly, a phase 3 adaptive, randomized, placebo-controlled study sponsored by the U.S.

T94

11041-11406

Sentence

denotes

National Institute of Allergy and Infectious Diseases (NIAID) in hospitalized adults (n = 1063) indicated that: (a) the patients in the remdesivir group had shorter median time to recovery (11 days) than the patients in the placebo group (15 days) and (b) remdesivir may decrease the mortality rate from 11.6% in the placebo group to 8% in the treatment group [40].

T95

11407-11469

Sentence

denotes

As of now, the COVID-19 Treatment Guidelines Panel of the U.S.

T96

11470-11696

Sentence

denotes

National Institute of Health recommends remdesivir for the treatment of COVID-19 in hospitalized patients with severe disease (requiring supplemental oxygen or on mechanical ventilation or extracorporeal membrane oxygenation).

T97

11697-11861

Sentence

denotes

The Panel also indicates that there are no sufficient data to recommend either for or against the use of remdesivir in patients with mild or moderate COVID-19 [41].

T98

11862-11879

Sentence

denotes

Of note, the U.S.

T99

11880-12084

Sentence

denotes

FDA warns against the concomitant use of remdesivir and chloroquine or hydroxychloroquine owing to in vitro evidence which suggests that chloroquine blocks the intracellular activation of remdesivir [42].

T100

12085-12262

Sentence

denotes

Moreover, data from the manufacturer’s compassionate use program suggested no safety concerns were identified for remdesivir in pediatric, pregnant, or postpartum patients [43].

T101

12264-12268

Sentence

denotes

2.2.

T102

12269-12304

Sentence

denotes

Galidesivir (Immucillin-A, BCX4430)

T103

12305-12418

Sentence

denotes

Galidesivir is an adenosine nucleoside analog (Figure 3) that is an active site inhibitor of RdRp (EC50 < 50 µM).

T104

12419-12558

Sentence

denotes

Similar to remdesivir, it is a prodrug that is metabolized by cellular kinases to the corresponding active form of nucleoside triphosphate.

T105

12559-12722

Sentence

denotes

The triphosphate form binds to the active site of the viral enzyme and gets incorporated into the growing viral RNA chain resulting in premature chain termination.

T106

12723-12884

Sentence

denotes

The drug is being developed by BioCryst, U.S., and being tested in a phase 1 clinical trial for COVID-19 or Yellow Fever in Brazil in collaboration with the U.S.

T107

12885-12928

Sentence

denotes

NIAID (NCT03891420; n = 132) [44,45,46,47].

T108

12929-13128

Sentence

denotes

The drug is used parenterally and has demonstrated a broad-spectrum, showing in vitro antiviral activity against at least 20 RNA viruses across eight different virus families including coronaviruses.

T109

13129-13280

Sentence

denotes

In animal studies, the drug was effective in protecting against dangerous viruses such as Zika, Yellow Fever, Marburg, and Ebola viruses [44,45,46,47].

T110

13282-13286

Sentence

denotes

2.3.

T111

13287-13307

Sentence

denotes

Ribavirin (Virazole)

T112

13308-13398

Sentence

denotes

It is an open-ring analog of guanosine nucleoside (Figure 3) that was approved by the U.S.

T113

13399-13465

Sentence

denotes

FDA in 1985 for the treatment of respiratory syncytial virus [48].

T114

13466-13579

Sentence

denotes

It is also used systemically for chronic hepatitis C virus (HCV) infection [49] and viral hemorrhagic fever [50].

T115

13580-13666

Sentence

denotes

The drug possesses broad-spectrum antiviral activity against both RNA and DNA viruses.

T116

13667-13858

Sentence

denotes

To exert its antiviral activity, the drug is to be activated by phosphorylation to generate the triphosphate nucleotide that acts as an inhibitor of RNA synthesis and viral mRNA capping [51].

T117

13859-13956

Sentence

denotes

Other mechanisms have also been proposed to account for its broad spectrum of antiviral activity.

T118

13957-14159

Sentence

denotes

Inhibition of host inosine monophosphate dehydrogenase by ribavirin-monophosphate and the resulting depletion of guanosine triphosphate (GTP) pool has been put forward to be another mechanism of action.

T119

14160-14270

Sentence

denotes

Decreased intracellular GTP pool decreases viral protein synthesis and limits the replication of viral genome.

T120

14271-14377

Sentence

denotes

Ribavirin is also a mutagen that leads to defective virions [52] and it has immunomodulatory actions [53].

T121

14378-14510

Sentence

denotes

Yet, the drug has a U.S. boxed warning pertaining to the risk of hemolytic anemia and potential complications during pregnancy [54].

T122

14511-14603

Sentence

denotes

Ribavirin is currently being evaluated in few trials for the treatment of COVID-19 patients.

T123

14604-14789

Sentence

denotes

It is being tested alone (NCT04356677; n = 50) or in combination with nitazoxanide and ivermectin (NCT04392427; n = 100) or with lopinavir/ritonavir and INF β-1b (NCT04276688; n = 127).

T124

14790-14893

Sentence

denotes

Recent computational work has shown that ribavirin binds with high affinity to RdRp of SARS-CoV-2 [55].

T125

14894-15000

Sentence

denotes

Furthermore, the MERS-CoV rhesus macaque model revealed promising results for ribavirin and IFN-α 2b [56].

T126

15001-15137

Sentence

denotes

Nevertheless, mixed results came out of treating MERS-CoV infections with a combination of ribavirin and IFNs (IFN-β1 or IFN-α 2a) [57].

T127

15138-15359

Sentence

denotes

Results from the in vitro testing of ribavirin in Vero E6 cells also indicated that the replication and/or the cellular spread of SARS-CoV was not inhibited at concentrations known to inhibit other sensitive viruses [58].

T128

15360-15742

Sentence

denotes

Interestingly, a recent open-label randomized controlled trial (NCT04276688; n = 127) indicated that early triple antiviral therapy of INF-β 1b, ribavirin, and lopinavir/ritonavir was safe and superior to lopinavir/ritonavir alone in alleviating the symptoms and shortening the duration of viral shedding and hospitalization in COVID-19 patients with mild to moderate symptoms [59].

T129

15744-15748

Sentence

denotes

2.4.

T130

15749-15780

Sentence

denotes

Clevudine (Levovir and Revovir)

T131

15781-15912

Sentence

denotes

It a thymidine nucleoside analog (Figure 3) that was approved in Korea for the treatment of hepatitis B virus (HBV) infection [60].

T132

15913-16049

Sentence

denotes

Similar to previous agents, it is a prodrug that requires phosphorylation to form the corresponding active nucleotide, the triphosphate.

T133

16050-16201

Sentence

denotes

Mechanistically, the triphosphate active form appears to noncompetitively inhibit the HBV reverse transcriptase protein priming and DNA synthesis [61].

T134

16202-16370

Sentence

denotes

Importantly, although clevudine showed a potent antiviral response, its long-term use for more than a year led to the development of viral resistance and myopathy [60].

T135

16371-16471

Sentence

denotes

The drug is being evaluated in a phase 2 as a treatment for COVID-19 in Korea (NCT04347915; n = 60).

T136

16473-16477

Sentence

denotes

2.5.

T137

16478-16567

Sentence

denotes

Emtricitabine (Emtriva) in Combination with Tenofovir Disoproxil or Tenofovir Alafenamide

T138

16568-16721

Sentence

denotes

Emtricitabine is a cytosine nucleoside analog (Figure 3) that is a competitive inhibitor of human immunodeficiency virus-1 (HIV-1) reverse transcriptase.

T139

16722-16810

Sentence

denotes

It is metabolized by cellular kinases-mediated phosphorylation to the triphosphate form.

T140

16811-17038

Sentence

denotes

Emtricitabine triphosphate is the active form that blocks the HIV replication by terminating its genetic chain elongation, and thus, it prevents the generation of complementary DNA from the viral RNA and reduces the viral load.

T141

17039-17078

Sentence

denotes

The drug was first approved by the U.S.

T142

17079-17149

Sentence

denotes

FDA as an orally bioavailable, once-daily antiretroviral drug in 2003.

T143

17150-17257

Sentence

denotes

It is now used in combination with other antiretroviral drugs for the treatment of HIV-1 infection [62,63].

T144

17258-17484

Sentence

denotes

Combinations with tenofovir disoproxil fumarate (Truvada), tenofovir alafenamide (Descovy; 2016), rilpivirine, and tenofovir alafenamide (Odefsey; 2016), or bictegravir and tenofovir alafenamide (Biktarvy; 2018) are available.

T145

17485-17743

Sentence

denotes

In particular, tenofovir disoproxil (Viread; 2001) is an adenine-based acyclic nucleotide analog (Figure S1) that, following activation, acts as a competitive inhibitor of reverse transcriptase, and subsequently, it leads to DNA chain elongation termination.

T146

17744-18068

Sentence

denotes

Activation of the drug starts with the hydrolysis of the external esters followed by spontaneous release of carbon dioxide and formaldehyde to form the corresponding tenofovir, a nucleoside monophosphate, which subsequently undergoes two phosphorylation steps to form tenofovir diphosphate, the active drug (Figure S1) [64].

T147

18069-18110

Sentence

denotes

It was first approved in 2001 by the U.S.

T148

18111-18197

Sentence

denotes

FDA and is prescribed for the oral treatment of HIV-1 and chronic HBV infections [65].

T149

18198-18381

Sentence

denotes

It is also available in many other combinations with emtricitabine, lamivudine (Cimduo; 2018), doravirine and lamivudine (Delstrigo; 2018), and efavirenz and lamivudine (Symfi; 2018).

T150

18382-18660

Sentence

denotes

The efficacy of emtricitabine and tenofovir disoproxil as a prophylactic combination against SARS-CoV-2 infection is being evaluated in a large randomized, double-blind, controlled with placebo clinical trial for health care providers exposed to COVID-19 patients (NCT04334928).

T151

18661-18833

Sentence

denotes

The two drugs have been reported by a recent computational work as potential inhibitors of RdRp of SARS-CoV-2 [55,66], yet this potential is to be experimentally confirmed.

T152

18834-19050

Sentence

denotes

Likewise, tenofovir alafenamide (Vemlidy; 2016) is an adenine-based acyclic nucleotide analog that, following activation, acts as a competitive inhibitor of reverse transcriptase and DNA chain elongation termination.

T153

19051-19229

Sentence

denotes

The activation of the drug is, however, different and it usually takes place in infected cells by a series of bio-transformations similar to those of remdesivir (Figure S2) [67].

T154

19230-19446

Sentence

denotes

The main advantage of the prodrug, relative to the former prodrug, is that it increases the drug’s oral bioavailability, intestinal diffusion, selectivity of targeting the infected cells, and intracellular half-life.

T155

19447-19528

Sentence

denotes

It also decreases the potential renal toxicity of the monophosphate intermediate.

T156

19529-19589

Sentence

denotes

Tenofovir alafenamide was first approved in 2016 by the U.S.

T157

19590-19657

Sentence

denotes

FDA and is prescribed for the oral treatment of HBV infection [68].

T158

19658-19896

Sentence

denotes

It is also available in many other combinations with emtricitabine (Descovy; 2016), bictegravir and emtricitabine (Biktarvy; 2018), emtricitabine and rilpivirine (Odefsey; 2016), and darunavir/cobicistat and emtricitabine (Symtuza; 2018).

T159

19897-20186

Sentence

denotes

The efficacy of emtricitabine and tenofovir alafenamide as a prophylactic combination against SARS-CoV-2 infection is being evaluated in a large randomized, double-blind, controlled with placebo clinical trial for health care providers exposed to COVID-19 patients (NCT04405271; n = 1378).

T160

20188-20192

Sentence

denotes

2.6.

T161

20193-20220

Sentence

denotes

Favipiravir (Avigan, T-705)

T162

20221-20283

Sentence

denotes

Favipiravir was originally developed by Fujifilm group, Japan.

T163

20284-20376

Sentence

denotes

It is a pyrazine-carboxamide derivative (Figure 4) with a broad-spectrum antiviral activity.

T164

20377-20443

Sentence

denotes

It selectively and potently inhibits the RdRp of RNA viruses [69].

T165

20444-20520

Sentence

denotes

Favipiravir is a prodrug that requires bioactivation in host-infected cells.

T166

20521-20575

Sentence

denotes

Its active form is favipiravir-ribose-5′-triphosphate.

T167

20576-20787

Sentence

denotes

The first step in the formation of the active species is potentially catalyzed by human hypoxanthine guanine phosphoribosyl-transferase [70], which converts favipiravir into ribose-5′-monophosphate intermediate.

T168

20788-20954

Sentence

denotes

The latter intermediate undergoes two phosphorylation steps mediated by the action of host kinases leading to the formation of the ribose-5′-triphosphate active form.

T169

20955-21094

Sentence

denotes

Favipiravir is effective against several strains of influenza viruses, including those that are resistant to existing anti-influenza drugs.

T170

21095-21266

Sentence

denotes

Favipiravir also showed an antiviral activity in experimental animals against other RNA viruses, including arenaviruses, alphaviruses, bunyaviruses, and flaviviruses [71].

T171

21267-21393

Sentence

denotes

Furthermore, preliminary results also indicated that favipiravir potentially possesses a moderate activity against Ebola [72].

T172

21394-21789

Sentence

denotes

Importantly, a recent nonrandomized, open-label study in patients (n = 80) with non-severe COVID-19 showed that favipiravir (1600 mg orally twice daily on the first day, then 600 mg orally twice daily for thirteen days) with INF-α had significantly better therapeutic effects on SARS-CoV-2 infection, in terms of disease progression and viral clearance, than lopinavir/ritonavir with INF-α [73].

T173

21790-22263

Sentence

denotes

Furthermore, an open-label, prospective, randomized, multicenter study in adults (n = 236) with COVID-19 pneumonia in China revealed that favipiravir (1600 mg orally twice daily on the first day, then 600 mg orally twice daily for 7–10 days) was associated with a higher 7-day clinical recovery rate compared to a control group treated with umifenovir, a potential inhibitor of the membrane fusion stage during the virus infection, (200 mg three times daily for 7–10 days).

T174

22264-22447

Sentence

denotes

The 7-day clinical recovery rate in patients with moderate COVID-19 pneumonia was 71% in the favipiravir-treated patients, whereas the rate was 56% in the umifenovir-treated patients.

T175

22448-22582

Sentence

denotes

Likewise, the 7-day clinical recovery rate in patients with severe to critical COVID-19 pneumonia was 6% versus 0%, respectively [74].

T176

22583-22779

Sentence

denotes

Currently, favipiravir is being studied alone or in combination with tocilizumab, hydroxychloroquine, or oseltamivir for the treatment of COVID-19 in more than 23 clinical trials across the world.

T177

22780-22969

Sentence

denotes

As of now, favipiravir is not available in the U.S. or European countries, perhaps because the animal experiments showed that the antiviral agent can be associated with teratogenic effects.

T178

22970-23049

Sentence

denotes

Favipiravir is contraindicated in women with known or suspected pregnancy [75].

T179

23050-23107

Sentence

denotes

Favipiravir is also associated with QT prolongation [76].

T180

23108-23263

Sentence

denotes

It is currently approved to treat novel or re-emerging influenza outbreaks in China and Japan, and it is available as an oral solid dosage form [73,74,76].

T181

23265-23269

Sentence

denotes

2.7.

T182

23270-23276

Sentence

denotes

AT-527

T183

23277-23501

Sentence

denotes

It is an investigational, orally active, purine nucleotide prodrug (Figure S3), which has exhibited antiviral activity against many single-stranded, enveloped RNA viruses, including human flaviviruses and coronaviruses [77].

T184

23502-23546

Sentence

denotes

It is a potent inhibitor of viral RdRp [78].

T185

23547-23689

Sentence

denotes

Following oral administration as hemi-sulfate salt, the drug gets converted to the monophosphate form via multiple metabolic activation steps.

T186

23690-23830

Sentence

denotes

The first step is catalyzed by the action of human carboxylesterase 1 (CES1) and/or cathepsin A (CatA) to produce the L-alanyl intermediate.

T187

23831-23996

Sentence

denotes

Spontaneous hydrolysis followed by histidine triad nucleotide-binding protein 1 (HINT1)-mediated hydrolysis results in the formation of the monophosphate metabolite.

T188

23997-24303

Sentence

denotes

Then, the monophosphate is transformed to guanosine analog by adenosine deaminase like protein 1 (ADALP1) and further phosphorylated by guanylate kinase 1 (GUK1) and nucleoside diphosphate kinase (NDPK) to the pharmacologically active form of AT-527 diphosphate (also reported as AT-9010) (Figure S3) [78].

T189

24304-24448

Sentence

denotes

The safety, pharmacokinetics, and antiviral activity of AT-527 was earlier established in HCV-infected subjects with and without cirrhosis [79].

T190

24449-24655

Sentence

denotes

The drug is currently being evaluated in a phase 2 double-blind, randomized, placebo-controlled study to determine its efficacy and safety in patients with moderate COVID-19 symptoms (NCT04396106; n = 190).

T191

24657-24661

Sentence

denotes

2.8.

T192

24662-24671

Sentence

denotes

EIDD-2801

T193

24672-24744

Sentence

denotes

It is the isopropyl-ester prodrug of β-D-N4-hydroxycytidine (Figure 5A).

T194

24745-24875

Sentence

denotes

The prodrug has improved oral bioavailability as it avoids phosphorylation of the N4-hydroxyl group in the gastrointestinal tract.

T195

24876-25038

Sentence

denotes

It is hydrolyzed in vivo to release the parent (EIDD-1931), which distributes into tissues, and upon tri-phosphorylation, it becomes the active triphosphate form.

T196

25039-25295

Sentence

denotes

The tri-phosphorylated form has a broad-spectrum antiviral activity against various RNA viruses, including influenza, Ebola, Venezuelan equine encephalitis virus, MERS-CoV, SARS-CoV, SARS-CoV-2 and related zoonotic group 2b or 2c bat coronaviruses [80,81].

T197

25296-25402

Sentence

denotes

It also demonstrated increased potency against a coronavirus with resistance mutations to remdesivir [82].

T198

25403-25569

Sentence

denotes

By the action of RdRp, the active form is incorporated into the genome of RNA viruses, leading to the accumulation of mutations known as viral error catastrophe [80].

T199

25570-25752

Sentence

denotes

The active form exists in two forms (Figure 5B): the oxime form which mimics uridine and pairs with adenosine, while the other tautomer mimics cytidine and pairs with guanosine [81].

T200

25753-25920

Sentence

denotes

In mice infected with MERS-CoV or SARS-CoV, EIDD-2801 administration was found to diminish the virus titer and body weight loss and to improve pulmonary function [80].

T201

25921-26049

Sentence

denotes

Reduced MERS-CoV yields in vitro and in vivo was because of the increase in transition mutation frequency in only the viral RNA.

T202

26050-26117

Sentence

denotes

The drug produced similar results in human airway epithelial cells.

T203

26118-26192

Sentence

denotes

The drug showed similar results as a prophylactic and as a treatment [80].

T204

26193-26501

Sentence

denotes

The drug was developed at the Emory Institute for Drug Development and it was tested in a phase 1 randomized, double-blind, placebo-controlled, first-in-human study designed to evaluate its safety, tolerability, and pharmacokinetics following oral administration to healthy volunteers (NCT04392219; n = 130).

T205

26502-26614

Sentence

denotes

It is now being tested in two phase 2 trials in COVID-19 patients (NCT04405570; n = 44 and NCT04405739; n = 60).

T206

26616-26618

Sentence

denotes

3.

T207

26619-26644

Sentence

denotes

Viral Protease Inhibitors

T208

26646-26650

Sentence

denotes

3.1.

T209

26651-26680

Sentence

denotes

Lopinavir/Ritonavir (Kaletra)

T210

26681-26830

Sentence

denotes

Lopinavir (Figure 6) is an orally bioavailable, small peptidomimetic antiretroviral agent that acts as an HIV-1 aspartate competitive inhibitor [83].

T211

26831-26966

Sentence

denotes

The drug inhibits the cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV.

T212

26967-27061

Sentence

denotes

The inhibition eventually results in the formation of immature, noninfectious viral particles.

T213

27062-27095

Sentence

denotes

The drug was approved by the U.S.

T214

27096-27203

Sentence

denotes

FDA in combination with ritonavir (Figure 6), which is another antiretroviral aspartate protease inhibitor.

T215

27204-27406

Sentence

denotes

Ritonavir does not only provide an additive effective, but it is also a pharmacokinetic booster, i.e., it inhibits the CYP3A-mediated metabolism of lopinavir and thus increases its plasma level [83,84].

T216

27407-27741

Sentence

denotes

Currently, lopinavir/ritonavir is being evaluated for the treatment of SARS-CoV-2 patients in more than 35 interventional trials alone or in conjugation with hydroxychloroquine, inhaled INF-α, INF-β 1b and hydroxychloroquine, or oseltamivir (an inhibitor of neuraminidase in influenza virus) (for details refer to clinicaltrials.gov).

T217

27742-27810

Sentence

denotes

The rationale for using lopinavir is attributed to multiple studies.

T218

27811-27941

Sentence

denotes

Lopinavir exhibited an antiviral activity against SARS-CoV-2 virus in Vero E6 cells with an estimated EC50 value of 26.63 μM [85].

T219

27942-28086

Sentence

denotes

Computational studies have also suggested that lopinavir may inhibit the viral main protease Mpro, perhaps by targeting its active site [86,87].

T220

28087-28177

Sentence

denotes

Earlier, lopinavir exhibited in vitro activity against SARS-CoV-1 and MERS-CoV [88,89,90].

T221

28178-28268

Sentence

denotes

It also showed beneficial effects in animal studies for the treatment of MERS-CoV [91,92].

T222

28269-28430

Sentence

denotes

Furthermore, there is an evidence of some clinical benefit for lopinavir/ritonavir when used with ribavirin and/or INFs against MERS-CoV and SARS-CoV [88,93,94].

T223

28431-28590

Sentence

denotes

Yet, coronavirus proteases, including Mpro, do not have a C2-symmetric protein architecture which is the target of lopinavir and all HIV-1 protease inhibitors.

T224

28591-28698

Sentence

denotes

This subsequently sheds doubts on the prospect of HIV-1 aspartate protease inhibitors in treating COVID-19.

T225

28699-28963

Sentence

denotes

In this direction, a randomized, open-label trial in China in COVID-19 patients (n = 199), who were hospitalized with severe illness, compared lopinavir/ritonavir (400 mg/100 mg twice a day for 14 days) along with the standard care to the standard care alone [94].

T226

28964-29261

Sentence

denotes

The trial found that the time to achieve clinical improvement was similar in the two groups and that no statistically significant improvement, with respect to the viral load, oxygen therapy duration, hospitalization duration, or time to death, was achieved by the use of the drug combination [95].

T227

29262-29411

Sentence

denotes

Furthermore, a retrospective cohort study in China evaluated the use of lopinavir/ritonavir with or without umifenovir in COVID-19 patients (n = 16).

T228

29412-29606

Sentence

denotes

On the seventh day, SARS-CoV-2 was not detected in the nasopharyngeal specimens of 35% of lopinavir/ritonavir-treated patients compared to 75% of lopinavir/ritonavir/umifenovir-treated patients.

T229

29607-29702

Sentence

denotes

Chest computerized tomography scans were also better in the latter group (29% versus 69%) [96].

T230

29703-29988

Sentence

denotes

Moreover, a randomized, open-label trial in COVID-19 adults (n = 127) with mild to moderate symptoms in Hong Kong suggested that adding ribavirin and INF-β-1b to lopinavir/ritonavir increased the efficacy of the treatment when it was initiated within 7 days of the symptoms onset [59].

T231

29989-30117

Sentence

denotes

Other studies also suggested a limited benefit of lopinavir/ritonavir with or without INFs in patients with COVID-19 [97,98,99].

T232

30118-30451

Sentence

denotes

Recently, a small, randomized study in hospitalized COVID-19 adults (n = 22) in China compared lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily for 10 days) against chloroquine (500 mg twice daily for 10 days) and found that chloroquine was linked to a shorter time to RT-PCR conversion and a faster recovery [100].

T233

30453-30457

Sentence

denotes

3.2.

T234

30458-30490

Sentence

denotes

Darunavir/Cobicistat (Prezcobix)

T235

30491-30610

Sentence

denotes

Darunavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease [101,102].

T236

30611-30837

Sentence

denotes

In addition to the active site, it has been reported that the flexible darunavir binds to another site on the surface of the enzyme, which accounts for its resilience against potential mutations in the targeted protease [103].

T237

30838-30880

Sentence

denotes

Darunavir was approved in 2015 by the U.S.

T238

30881-30967

Sentence

denotes

FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat.

T239

30968-31155

Sentence

denotes

Although structurally similar to ritonavir, cobicistat lacks antiviral activity due to the lack of the central phenyl-propanol moiety, a key structural feature of HIV protease inhibitors.

T240

31156-31251

Sentence

denotes

Darunavir/cobicistat is under clinical investigation for the treatment of SARS-CoV-2 infection.

T241

31252-31407

Sentence

denotes

This is potentially attributed to darunavir ability to in vitro inhibit SARS-CoV-2 in Vero E6 cells, albeit at high concentrations (EC50 = 46.41 µM) [104].

T242

31408-31512

Sentence

denotes

Mechanistically, this could be because darunavir potentially inhibits 3CLpro and/or PLpro of SARS-CoV-2.

T243

31513-31581

Sentence

denotes

The two enzymes are important for the viral glycoprotein processing.

T244

31582-31743

Sentence

denotes

However, in another in vitro study, darunavir/cobicistat demonstrated no activity against SARS-CoV-2 at clinically relevant concentrations in Caco-2 cells [105].

T245

31744-31900

Sentence

denotes

Furthermore, the results from a randomized controlled trial in China showed that darunavir/cobicistat was not effective in treating COVID-19 patients [106].

T246

31901-32198

Sentence

denotes

Regardless, darunavir is being tried in about three trials in combination with cobicistat (NCT04252274; n = 30), ritonavir/hydroxychloroquine (NCT04435587; n = 80), ritonavir/oseltamivir, ritonavir/oseltamivir/hydroxychloroquine, or ritonavir/favipiravir/hydroxychloroquine (NCT04303299; n = 320).

T247

32199-32280

Sentence

denotes

TMC310911 (also known as ASC-09) (Figure 6) is structurally similar to darunavir.

T248

32281-32367

Sentence

denotes

It is HIV-1 aspartate protease competitive inhibitor with improved antiviral activity.

T249

32368-32562

Sentence

denotes

TMC310911 has potent activity against the wild-type HIV-1 and against an extended spectrum of recombinant HIV-1 clinical isolates, including multiple protease inhibitors-resistant strains [107].

T250

32563-32651

Sentence

denotes

Similar to darunavir, it was evaluated with the pharmacokinetic booster ritonavir [108].

T251

32652-32751

Sentence

denotes

Currently, it is being tested in two clinical trials in China in patients infected with SARS-CoV-2.

T252

32752-32861

Sentence

denotes

It is being tested in combination with ritonavir (NCT04261907; n = 160) or oseltamivir (NCT04261270; n = 60).

T253

32862-33028

Sentence

denotes

In a recent computational exercise, TMC-310911 was reported as a potential inhibitor of Mpro of SARS-CoV-2 [66], yet this potential is to be experimentally confirmed.

T254

33030-33034

Sentence

denotes

3.3.

T255

33035-33055

Sentence

denotes

Atazanavir (Reyataz)

T256

33056-33166

Sentence

denotes

Atazanavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease.

T257

33167-33210

Sentence

denotes

Atazanavir was approved in 2003 by the U.S.

T258

33211-33357

Sentence

denotes

FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat (combination is being marketed under the name Evotaz; 2015).

T259

33358-33620

Sentence

denotes

Currently, it is being evaluated alone (NCT04468087; n = 189) or in combination with NA-831 (neuroprotective agent; traneurocin) or dexamethasone for the treatment of COVID-19 infection (NCT04452565; n = 525) or with nitazoxanide/ritonavir (NCT04459286; n = 98).

T260

33621-33808

Sentence

denotes

The drug alone or in combination with ritonavir demonstrated in vitro activity against SARS-CoV-2 in Vero E6 cells, human epithelial pulmonary cells (A549), and human monocytes [109,110].

T261

33809-33879

Sentence

denotes

In these studies, atazanavir has been identified as inhibitor of Mpro.

T262

33880-34005

Sentence

denotes

The drug and its combination have been projected to be 10-fold more potent than lopinavir and its combination with ritonavir.

T263

34006-34091

Sentence

denotes

The drug also inhibited the virus-induced enhancement of IL-6 and TNF-α levels [109].

T264

34092-34248

Sentence

denotes

In a separate computational study, atazanavir was reported as a potential inhibitor of SARS-CoV-2 helicase, a viral enzyme that unwinds nucleic acids [111].

T265

34250-34254

Sentence

denotes

3.4.

T266

34255-34275

Sentence

denotes

Danoprevir/Ritonavir

T267

34276-34388

Sentence

denotes

Danoprevir (Ganovo) is an orally bioavailable 15-membered macrocyclic peptidomimetic antiviral drug (Figure S4).

T268

34389-34471

Sentence

denotes

It is an inhibitor of NS3/4A HCV protease, an important processing enzyme complex.

T269

34472-34533

Sentence

denotes

It inhibits the protease with an IC50 value of 0.29 nM [112].

T270

34534-34597

Sentence

denotes

It was approved in China in 2018 to treat chronic HCV patients.

T271

34598-34681

Sentence

denotes

At higher concentrations, it also appears to inhibit the aspartate protease of HIV.

T272

34682-34821

Sentence

denotes

The NS3/4A protease of HCV is claimed to share a certain level of structural and/or functional similarity to the protease(s) of SARS-CoV-2.

T273

34822-34933

Sentence

denotes

Thus, HCV protease inhibitors, including danoprevir, have been proposed as potential therapeutics for COVID-19.

T274

34934-35230

Sentence

denotes

This has also been supported by computational work which indicated that HCV protease inhibitors have high binding affinity to 3CLpro of SARS-CoV-2 [113] and by in vitro and clinical studies which showed that patients with SARS-CoV or MERS-CoV may benefit from HCV protease inhibitors [88,90,114].

T275

35231-35433

Sentence

denotes

Currently, danoprevir in combination with ritonavir, is being evaluated in two clinical trials (NCT04345276; n = 10) and (with nebulized INF; NCT04291729; n = 11) for the treatment of COVID-19 patients.

T276

35434-35610

Sentence

denotes

As mentioned earlier, ritonavir is an antiviral and pharmacokinetic booster that extends the systemic exposure of patients to potential therapeutic concentration of danoprevir.

T277

35611-35809

Sentence

denotes

In fact, a recent clinical study results under review has indicated that danoprevir/ritonavir combination alleviated the symptoms in COVID-patients and accelerated their recovery in 4–12 days [115].

T278

35811-35815

Sentence

denotes

3.5.

T279

35816-35837

Sentence

denotes

Maraviroc (Selzentry)

T280

35838-36123

Sentence

denotes

It is a small, synthetic, azabicyclic molecule (Figure S4) that exhibits antiretroviral activity by blocking the interaction between HIV-1 glycoprotein 120 and chemokine receptor 5 (C-C motif receptor 5), on human CD4-presenting cells, that is necessary for HIV-1 to enter cells [116].

T281

36124-36157

Sentence

denotes

The drug was approved by the U.S.

T282

36158-36201

Sentence

denotes

FDA in 2007 as an oral treatment for HIV-1.

T283

36202-36332

Sentence

denotes

The drug is currently being evaluated in three clinical trials (NCT04441385, NCT04435522, and NCT04475991) for COVID-19 treatment.

T284

36333-36418

Sentence

denotes

Recently, it was shown that maraviroc may act as a potential inhibitor of Mpro [117].

T285

36419-36632

Sentence

denotes

However, it appears that it is more realistic to assume that the drug is a viral entry inhibitor and potentially acts by blocking the interaction between the viral spike S protein and the host ACE2 receptor [118].

T286

36634-36636

Sentence

denotes

4.

T287

36637-36667

Sentence

denotes

Miscellaneous Antiviral Agents

T288

36669-36673

Sentence

denotes

4.1.

T289

36674-36700

Sentence

denotes

Selinexor (Xpovio, KPT330)

T290

36701-36797

Sentence

denotes

Selinexor is bis(trifluoromethyl)phenyl-triazole-based antineoplastic small molecule (Figure 7).

T291

36798-36839

Sentence

denotes

It was first approved in 2019 by the U.S.

T292

36840-36931

Sentence

denotes

FDA and is being prescribed with dexamethasone for refractory or relapsed multiple myeloma.

T293

36932-37073

Sentence

denotes

Selinexor is an orally bioavailable, selective inhibitor of chromosome region maintenance 1 (CRM1) protein (also known as exportin 1 (XPO1)).

T294

37074-37200

Sentence

denotes

CRM1 is the main export factor that shuttles nuclear proteins to the cytoplasm and is typically overexpressed in cancer cells.

T295

37201-37325

Sentence

denotes

Its selective inhibition can assist in restoring the endogenous tumor-suppressing processes so as to eliminate cancer cells.

T296

37326-37609

Sentence

denotes

Specifically, selinexor selectively and irreversibly modifies the essential Cys528 residue in CRM1, and thus, it blocks CRM1-mediated nuclear export of cargo proteins such as tumor suppressor proteins (p21, p53, pRB, BRCA1/2, FOXO, and others) from the cell nucleus to the cytoplasm.

T297

37610-37685

Sentence

denotes

This leads to the accumulation of tumor suppressor proteins in the nucleus.

T298

37686-37837

Sentence

denotes

It also results in decreased levels of oncoproteins, cell cycle arrest, and apoptosis of cancer cells without affecting the normal cells [119,120,121].

T299

37838-38088

Sentence

denotes

Considering the current viral pandemic, CRM1 has been put forward as a facilitator of the export of viral proteins from the nucleus of the host cell to the cytoplasm as well as an amplifier of the activities of pro-inflammatory transcription factors.

T300

38089-38193

Sentence

denotes

Thus, the CRM1 inhibitor selinexor may exert relevant antiviral and anti-inflammatory effects [122,123].

T301

38194-38362

Sentence

denotes

In fact, CRM1 inhibitors have exhibited activity against >20 different viruses, including RNA viruses such as respiratory syncytial virus and influenza virus [122,123].

T302

38363-38490

Sentence

denotes

Furthermore, CRM1 inhibition has also been identified in in vitro assays to have a potential activity against SARS-CoV-2 [124].

T303

38491-38611

Sentence

denotes

CRM1 was found to contribute to exporting several SARS-CoV proteins, such as S, N, 9b, Orf3 and Orf6 out of the nucleus.

T304

38612-38698

Sentence

denotes

Thus, CRM1 inhibition is expected to inhibit the viral assembly [125,126,127,128,129].

T305

38699-38880

Sentence

denotes

Moreover, CRM1 has also been found to contribute to the nuclear export and functional inactivation of antioxidant, anti-inflammatory, and cytoprotective transcription factors [130].

T306

38881-39023

Sentence

denotes

High levels of CRM1 are found in multiple inflammatory conditions and may magnify inflammatory responses leading to severe organ damage [131].

T307

39024-39234

Sentence

denotes

In this direction, selinexor and similar inhibitors have exhibited potent anti-inflammatory activity by suppressing the activation of NFkB and p38 signaling, leading to reduced cytokines in a variety of models.

T308

39235-39342

Sentence

denotes

For example, in a mouse model of sepsis, selinexor increased survival following a lethal dose of endotoxin.

T309

39343-39528

Sentence

denotes

Selinexor reduced the inflammatory cytokine secretion of IL-6, TNF-α, and HMGB1 while reducing the numbers of macrophage and polymorphonuclear neutrophils in the mice peritoneal cavity.

T310

39529-39654

Sentence

denotes

Selinexor also mitigated lipopolysaccharide-induced lung injury that is similar to acute respiratory distress syndrome [132].

T311

39655-39770

Sentence

denotes

Currently, selinexor is being evaluated in at least two phase 2 randomized trials in the U.S. in COVID-19 patients.

T312

39771-40203

Sentence

denotes

One is to evaluate the activity, safety and reduction in mortality of two regimens of low-dose selinexor in patients with moderate or severe COVID-19 (NCT04355676, n = 80) and the other is to evaluate the activity of low-dose selinexor and its effect on the clinical recovery, viral load, length of hospitalization, and rate of morbidity and mortality in participants with severe COVID-19 compared to placebo (NCT04349098, n = 230).

T313

40205-40209

Sentence

denotes

4.2.

T314

40210-40231

Sentence

denotes

Nitazoxanide (Alinia)

T315

40232-40336

Sentence

denotes

It is a nitro-thiazolyl-salicylamide derivative (Figure 7) with a broad-spectrum antimicrobial activity.

T316

40337-40430

Sentence

denotes

The drug is effective against various helminthic, protozoal, bacterial, and viral infections.

T317

40431-40458

Sentence

denotes

It was approved by the U.S.

T318

40459-40581

Sentence

denotes

FDA in 2002 to be used orally for the treatment of diarrhea caused by Cryptosporidium parvum or Giardia lamblia [133,134].

T319

40582-40675

Sentence

denotes

It is also off-label used for cryptosporidiosis-associated diarrhea in HIV-infected patients.

T320

40676-40800

Sentence

denotes

The drug has been reported as a broad-spectrum antiviral agent that inhibits the replication of several RNA and DNA viruses.

T321

40801-40943

Sentence

denotes

Specifically, nitazoxanide has been found to affect influenza A and B viruses as well as neuraminidase inhibitors-resistant influenza viruses.

T322

40944-41180

Sentence

denotes

It has also been found to inhibit the replication of coronavirus, dengue virus, HBV, HCV, HIV, Japanese encephalitis virus, norovirus, parainfluenza, rotavirus, respiratory syncytial virus, and yellow fever in cell culture assays [135].

T323

41181-41301

Sentence

denotes

Some of its activity is also potentially attributed to its active metabolite (tizoxanide), desacetyl-nitazoxanide [136].

T324

41302-41561

Sentence

denotes

Currently, nitazoxanide is being studied alone or in combination with hydroxychloroquine, ivermectin, ribavirin/ivermectin, or atazanavir/ritonavir for the prevention/treatment of COVID-19 in about 17 clinical trials (for details refer to clinicaltrials.gov).

T325

41562-41609

Sentence

denotes

The drug is associated with several mechanisms.

T326

41610-41782

Sentence

denotes

The anti-protozoal activity demonstrated by this drug is promoted by the inhibition of pyruvate:ferredoxin oxidoreductase enzyme-dependent electron transfer reaction [137].

T327

41783-42001

Sentence

denotes

However, in the case of influenza, nitazoxanide and its metabolite inhibit the viral hemagglutinin maturation at the post-translational phase with no effect on the M2 protein or on the neuraminidase glycoprotein [138].

T328

42002-42277

Sentence

denotes

Furthermore, nitazoxanide modulates other targets and pathways in vitro including glutamate-gated chloride ion channels and glutathione-S-transferase in nematodes, respiration and other pathways in bacterial and cancer cells, and viral and host transcriptional factors [134].

T329

42278-42444

Sentence

denotes

In fact, nitazoxanide was shown to in vitro inhibit the replication of coronaviruses, including MERS-CoV in cells and the expression of the viral N protein [136,139].

T330

42445-42589

Sentence

denotes

The drug was also reported as a non-competitive inhibitor of thiol oxidoreductase ERp57 and thus demonstrated anti-paramyxovirus activity [140].

T331

42590-42744

Sentence

denotes

Moreover, nitazoxanide was reported to inhibit the production of pro-inflammatory cytokines in peripheral blood mononuclear cells and animal models [136].

T332

42745-42888

Sentence

denotes

In peripheral blood mononuclear cells exposed to influenza virus, nitazoxanide potentiated the release of INF-α and INF-β by fibroblasts [135].

T333

42889-43038

Sentence

denotes

In addition, nitazoxanide appears also to act as a bronchodilator in testing models by blocking the calcium-activated chloride channel TMEM16A [141].

T334

43040-43044

Sentence

denotes

4.3.

T335

43045-43052

Sentence

denotes

NSAIDs:

T336

43053-43096

Sentence

denotes

Indomethacin (Indocin) and Naproxen (Aleve)

T337

43097-43210

Sentence

denotes

In one hand, indomethacin is a synthetic, small molecule of N-benzoyl-indole-3-acetic acid derivative (Figure 7).

T338

43211-43244

Sentence

denotes

It was first approved by the U.S.

T339

43245-43274

Sentence

denotes

FDA in 1984 for use as NSAID.

T340

43275-43330

Sentence

denotes

It also possesses analgesic and antipyretic properties.

T341

43331-43374

Sentence

denotes

It is used for acute mild to moderate pain.

T342

43375-43506

Sentence

denotes

It is also used for ankylosing spondylitis, bursitis, tendonitis, osteoarthritis, and rheumatoid arthritis, among other conditions.

T343

43507-43660

Sentence

denotes

The known mechanism is the reversible inhibition of cyclooxygenase-1 and 2 enzymes, which leads to decreased formation of prostaglandin precursors [142].

T344

43661-43912

Sentence

denotes

Orally administered indomethacin is being evaluated in combination with hydroxychloroquine and azithromycin in an open-label, single-arm, phase 2 study to determine its efficacy and safety in subjects with mild COVID-19 symptoms (NCT04344457; n = 80).

T345

43913-44224

Sentence

denotes

Considering activity against coronaviruses, in vitro studies demonstrated that indomethacin has a potent direct antiviral activity against the SARS coronavirus as determined in monkey Vero E6 cells and human lung epithelial A549 cells as well as against the canine coronavirus as determined in A72 canine cells.

T346

44225-44324

Sentence

denotes

Indomethacin blocked the viral RNA synthesis, but not the viral adhesion/entry into the host cells.

T347

44325-44385

Sentence

denotes

This effect is independent of the cyclooxygenase inhibition.

T348

44386-44522

Sentence

denotes

At a dose rate of 1 mg/kg, indomethacin resulted in more than 1000-fold reduction in the virus yield in coronavirus-infected dogs [143].

T349

44523-44752

Sentence

denotes

Likewise, indomethacin has been reported to be a potent inhibitor of SARS CoV-2 replication in Vero E6 cells with an IC50 value of 1 µM, which is 10-fold less than its peak plasma concentration, and a selective index of 500-fold.

T350

44753-45011

Sentence

denotes

Using a dose of 1 mg/kg in canine coronavirus-infected dogs, indomethacin accelerated the symptoms relieve and saved all infected animals, relative to ribavirin or anti-canine coronavirus serum/canine hemoglobin/canine blood immunoglobulin/INF regimen [144].

T351

45012-45147

Sentence

denotes

Previously, indomethacin also showed antiviral activity against rotavirus infection and vesicular stomatitis virus infection [145,146].

T352

45148-45338

Sentence

denotes

The antiviral activity of indomethacin was proposed to be a result of its binding to peroxisome proliferator activated receptor-γ, aldose reductase, and/or the viral NSP7/NSP8 complex [144].

T353

45339-45541

Sentence

denotes

The inhibition of the NSP7/NSP8 complex has been relatively verified and happened by indomethacin potentially targeting the interface between the host prostaglandin E synthase 2 and the viral NSP7/NSP8.

T354

45542-45663

Sentence

denotes

In fact, prostaglandin E synthase 2 itself is inhibited by indomethacin in Vero cells with an IC50 value of 750 nM [144].

T355

45664-45876

Sentence

denotes

Lastly, in addition to the inhibition of the pro-inflammatory prostaglandin biosynthesis, indomethacin was also found to halt the increase in IL-6 expression caused by lipopolysaccharide-treated U937 cells [147].

T356

45877-46005

Sentence

denotes

Accordingly, the effect of indomethacin on IL-6 may translate into beneficial effect in treating the cytokine storm of COVID-19.

T357

46006-46138

Sentence

denotes

In the other hand, naproxen is another synthetic, small molecule NSAID that is a derivative of 2-naphthalene-acetic acid (Figure 7).

T358

46139-46172

Sentence

denotes

It was first approved by the U.S.

T359

46173-46435

Sentence

denotes

FDA in 1976 for oral use in the treatment of a host of painful inflammatory conditions such as ankylosing spondylitis, bursitis, polyarticular juvenile idiopathic arthritis, osteoarthritis, rheumatoid arthritis, tendonitis, dysmenorrhea pain, and gout [148,149].

T360

46436-46613

Sentence

denotes

The efficacy of naproxen in the treatment of critically ill, hospitalized COVID-19 patients is being evaluated in a randomized, open label clinical trial (NCT04325633; n = 584).

T361

46614-46750

Sentence

denotes

The drug has been reported to exhibit antiviral activity against influenza A and B viruses with IC50 values in the low micromolar range.

T362

46751-46857

Sentence

denotes

In this arena, naproxen antagonized CRM1-mediated nuclear export of proteins of influenza A and B viruses.

T363

46858-46954

Sentence

denotes

Naproxen also provided therapeutic protection to mice infected with influenza B virus [150,151].

T364

46955-47109

Sentence

denotes

In hospitalized patients with influenza, it was found that adding clarithromycin and naproxen to oseltamivir shortened the hospitalization time [150,151].

T365

47110-47238

Sentence

denotes

Naproxen also inhibited the replication of Zika virus by reducing the expression of AXL, the entry cofactor of Zika virus [152].

T366

47239-47420

Sentence

denotes

Naproxen’s antiviral activity against SARS-CoV-2 has also been proposed by a recent computational work and has been attributed its ability to bind to the viral nucleocapsid protein.

T367

47421-47626

Sentence

denotes

In fact, it was recently reported that naproxen inhibits SARS-CoV-2 infection in Vero E6 cells and in reconstituted human airway epithelia with IC50 values comparable to those effective in influenza [153].

T368

47627-47788

Sentence

denotes

Lastly, similar to indomethacin, the anti-inflammatory effects of naproxen may also translate into beneficial effects in treating the cytokine storm of COVID-19.

T369

47790-47794

Sentence

denotes

4.4.

T370

47795-47861

Sentence

denotes

Vidofludimus Calcium (Immunic AG, IMU-838) and Brequinar (DuP-785)

T371

47862-48055

Sentence

denotes

Vidofludimus is a synthetic small molecule that is under investigation for treating inflammatory bowel disease, multiple sclerosis, and other inflammatory and autoimmune diseases [154,155,156].

T372

48056-48182

Sentence

denotes

It is a biphenyl-carbamoyl-cyclopentene derivative (Figure 7) that is being developed as oral formulation for therapeutic use.

T373

48183-48415

Sentence

denotes

Currently, a prospective, randomized, multi-center, double-blinded, and placebo-controlled study is ongoing to evaluate the safety and efficacy of vidofludimus as an adjunct therapy in COVID-19 patients (NCT04379271; n = 230) [157].

T374

48416-48608

Sentence

denotes

The investigational drug selectively inhibits dihydroorotate dehydrogenase, an important enzyme for the de novo biosynthesis of pyrimidine-based nucleotides, in activated B and T immune cells.

T375

48609-48729

Sentence

denotes

Such inhibition diminishes the pyrimidine pool in these cells, which subsequently exposes the cells to metabolic stress.

T376

48730-48883

Sentence

denotes

It also diminishes the release of T helper 1 (Th1) and T helper 17 (Th17) proinflammatory cytokines of IL-17 and IFN-γ, which reduces inflammation [154].

T377

48884-49102

Sentence

denotes

Interestingly, dihydroorotate dehydrogenase inhibition also results in a direct antiviral effect, which has been exhibited in cells infected with hemorrhagic fever-causing viruses, cytomegalovirus, and influenza virus.

T378

49103-49247

Sentence

denotes

In fact, IMU-838′s antiviral activity has been demonstrated in vitro against arenavirus, cytomegalovirus, influenza A virus, HCV, and HIV [157].

T379

49248-49330

Sentence

denotes

IMU-838 has also effectively promoted antiviral activity against SARS-CoV-2 [157].

T380

49331-49414

Sentence

denotes

Specifically, IMU-838 inhibited the replication of clinical isolates of SARS-CoV-2.

T381

49415-49600

Sentence

denotes

In cellular assays, IMU-838 promoted the anti-SARS-CoV-2 activity at concentrations lower than those that have been considered in previous and ongoing clinical trials [154,155,156,157].

T382

49601-49888

Sentence

denotes

Overall, IMU-838′s antiviral activity against SARS-CoV-2 as well as its selective immunomodulatory effect targeting activated immune cells appear to be interesting, particularly that it potentially prevents the virus reactivation that may happen with other immunomodulatory agents [157].

T383

49889-50041

Sentence

denotes

Likewise, brequinar is a synthetic, small molecule, and quinoline-carboxylic acid derivative (Figure 7) that also inhibits dihydroorotate dehydrogenase.

T384

50042-50130

Sentence

denotes

It eventually blocks the de novo biosynthesis of pyrimidine-based nucleotides [158,159].

T385

50131-50190

Sentence

denotes

Accordingly, brequinar possesses immunosuppressive effects.

T386

50191-50349

Sentence

denotes

Furthermore, it also possesses antineoplastic properties that can be exploited to enhance the in vivo antitumor activity of other antineoplastic agents [160].

T387

50350-50415

Sentence

denotes

Alternatively, the drug has also antiparasitic effects [160,161].

T388

50416-50573

Sentence

denotes

More importantly, the drug exhibits a broad-spectrum antiviral activity against influenza viruses [162], HIV-1 [163], and foot-and-mouth disease virus [164].

T389

50574-50727

Sentence

denotes

In fact, a pre-print under review has documented the activity of dihydroorotate dehydrogenase inhibitors against RNA viruses, including SARS-CoV-2 [165].

T390

50728-50911

Sentence

denotes

Currently, the drug is being evaluated in a randomized, open-label trial to assess its safety and anti-coronavirus activity in hospitalized adults with COVID-19 (NCT04425252; n = 24).

T391

50913-50917

Sentence

denotes

4.5.

T392

50918-50937

Sentence

denotes

Famotidine (Pepcid)

T393

50938-51053

Sentence

denotes

Famotidine is a synthetic guandino-thiazole derivative (Figure 7) that acts as a potent and competitive H2-blocker.

T394

51054-51087

Sentence

denotes

It was first approved by the U.S.

T395

51088-51141

Sentence

denotes

FDA in 1986 and now is used as over-the-counter drug.

T396

51142-51256

Sentence

denotes

It can be used orally or parenterally to treat gastroesophageal reflux disease, heartburn, and peptic ulcer [166].

T397

51257-51526

Sentence

denotes

Recently, a retrospective non-randomized study by Columbia University, Northwell Health, and Massachusetts General Hospital showed that famotidine, and not proton pump inhibitors, reduced the risk of intubation or death in hospitalized COVID-19 patients (n = 84) [167].

T398

51527-51818

Sentence

denotes

Furthermore, a case series indicated that COVID-19 patients (n = 10) who frequently self-administered a high-dose of oral famotidine (most frequent dose was 80 mg three times/day for a median of 11 days) reported significant symptoms improvement within 24 hours of starting famotidine [168].

T399

51819-52161

Sentence

denotes

Therefore, intravenously administered famotidine with standard of care (orally administered hydroxychloroquine and has progressed to include remdesivir) is currently being studied in a multi-site, randomized, double-blind, multi-arm historical control, comparative trial that is sponsored by Northwell Health, New York (NCT04370262; n = 942).

T400

52162-52353

Sentence

denotes

Famotidine has been identified via virtual screening and molecular modeling, docking, and scoring as a potential inhibitor of Mpro [169], yet this potential is to be experimentally confirmed.

T401

52355-52359

Sentence

denotes

4.6.

T402

52360-52368

Sentence

denotes

VERU-111

T403

52369-52542

Sentence

denotes

It is an orally bioavailable, 3-substituted indole derivative (Figure 8A) and microtubule depolymerization agent that recognizes colchicine-binding site on tubulin subunits.

T404

52543-52599

Sentence

denotes

It has been under clinical development for cancer [170].

T405

52600-52811

Sentence

denotes

Drugs targeting microtubules have broad antiviral activity because they disrupt the intracellular transport of viruses, including SARS CoV-2, along microtubules, which is critical for viruses to cause infection.

T406

52812-52985

Sentence

denotes

Microtubule depolymerization agents also have strong anti-inflammatory effects that can be beneficial in mitigating the cytokine storm induced by SARS-CoV-2 infection [171].

T407

52986-53196

Sentence

denotes

The drug is currently being evaluated in a phase 2 randomized, placebo-controlled study for the treatment of SARS-CoV-2 in patients at elevated risk of acute respiratory distress syndrome (NCT04388826; n = 40).

T408

53197-53309

Sentence

denotes

Of note, it is mechanistically similar to colchicine, which has also been considered in COVID-19 patients [172].

T409

53311-53315

Sentence

denotes

4.7.

T410

53316-53335

Sentence

denotes

Leflunomide (Arava)

T411

53336-53422

Sentence

denotes

It is a synthetic, small molecule and an isoxazole-carboxamide derivative (Figure 8B).

T412

53423-53450

Sentence

denotes

It was approved by the U.S.

T413

53451-53524

Sentence

denotes

FDA in 1998 for the oral treatment of rheumatoid arthritis [173,174,175].

T414

53525-53731

Sentence

denotes

It is also used off-label as a replacement therapy in kidney transplant recipients with polyomavirus BK [176] and for cytomegalovirus disease in transplant recipients resistant to standard antivirals [177].

T415

53732-53834

Sentence

denotes

Mechanistically, it is a disease-modifying agent with anti-inflammatory and antiproliferative effects.

T416

53835-54013

Sentence

denotes

It inhibits pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, an important enzyme in the de novo synthesis of uridine monophosphate [178].

T417

54014-54153

Sentence

denotes

Leflunomide is a prodrug and the active metabolite (isoxazole ring is open: teriflunomide (Aubagio)) is responsible for its activity [179].

T418

54154-54215

Sentence

denotes

It inhibits rapidly dividing cells such as activated T cells.

T419

54216-54279

Sentence

denotes

It has also been found to block the transcription factor NF-κB.

T420

54280-54321

Sentence

denotes

It also inhibits tyrosine kinase enzymes.

T421

54322-54493

Sentence

denotes

The drug inhibits the replication of cytomegalovirus, herpes simplex virus 1, and polyomavirus BK by interfering with nucleocapsid tegumentation and virion assembly [179].

T422

54494-54688

Sentence

denotes

Given the above activities, a high dose of leflunomide is being evaluated for the treatment of ambulatory patients with mild COVID-19 at the University of Chicago Medicine (NCT04361214; n = 20).

T423

54690-54694

Sentence

denotes

4.8.

T424

54695-54715

Sentence

denotes

Sirolimus (Rapamune)

T425

54716-54802

Sentence

denotes

Sirolimus is a natural macrolide (Figure S5) obtained from Streptomyces hygroscopicus.

T426

54803-54836

Sentence

denotes

It was first approved by the U.S.

T427

54837-54923

Sentence

denotes

FDA in 1999 and is orally used for lymphangioleiomyomatosis and renal transplantation.

T428

54924-55041

Sentence

denotes

Mechanistically, the drug is an immunosuppressive agent and an inhibitor of the mammalian target of rapamycin (mTOR).

T429

55042-55182

Sentence

denotes

Sirolimus forms an immunosuppressive complex with FK-binding protein-12, and subsequently, the complex inhibits the regulatory kinase, mTOR.

T430

55183-55304

Sentence

denotes

This inhibition suppresses cytokine mediated proliferation of T and B cells as well as the antibody production [180,181].

T431

55305-55461

Sentence

denotes

Furthermore, the drug may influence the virus because mTOR complex 1 is involved in the replication of various viruses, including coronavirus [182,183,184].

T432

55462-55582

Sentence

denotes

Furthermore, in vitro studies demonstrated a specific inhibitory activity against MERS-CoV infection by sirolimus [184].

T433

55583-55836

Sentence

denotes

In an open-label, prospective randomized study in H1N1 pneumonia patients, treatment with sirolimus and corticosteroids combination for two weeks alleviated hypoxia, shortened the mechanical ventilation duration, and improved multi-organ function [185].

T434

55837-55997

Sentence

denotes

Accordingly, sirolimus is being tested for the treatment of COVID-19 patients either alone or in combination with hydroxychloroquine in several clinical trials.

T435

55998-56158

Sentence

denotes

Likewise, RTB101 (dactolisib), another mTOR inhibitor and phosphoinositide 3-kinase inhibitor, is also being tested in COVID-19 patients (NCT04409327; n = 550).

T436

56160-56164

Sentence

denotes

4.9.

T437

56165-56186

Sentence

denotes

Plitidepsin (Aplidin)

T438

56187-56290

Sentence

denotes

It is a cyclic depsipeptide natural product (Figure S5) that is extracted from Aplidium albicans [186].

T439

56291-56425

Sentence

denotes

It is used for acute lymphoblastic leukemia and, with dexamethasone, for patients with refractory and relapsed multiple myeloma [187].

T440

56426-56538

Sentence

denotes

Recently, the molecule was reported to have in vitro nanomolar potency against the human coronavirus 229E [188].

T441

56539-56789

Sentence

denotes

The mechanism is thought to be similar to its anticancer activity, i.e., targeting eukaryotic translation elongation factor 1-α1, which has been reported to play an unexpected role in the replication and pathogenesis of various RNA viruses [189,190].

T442

56790-56880

Sentence

denotes

The drug is being tested in phase 1 trial in patients with COVID-19 (NCT04382066; n = 27).

T443

56882-56887

Sentence

denotes

4.10.

T444

56888-56912

Sentence

denotes

Cyclosporine A (Gengraf)

T445

56913-57013

Sentence

denotes

Cyclosporine A is a cyclic peptide that is naturally obtained from the fungus Beauveria nivea [191].

T446

57014-57102

Sentence

denotes

It is immunosuppressant and calcineurin inhibitor that inhibits T cell activation [192].

T447

57103-57201

Sentence

denotes

It binds to the intracellular receptor cyclophilin-1 producing a cyclosporine-cyclophilin complex.

T448

57202-57372

Sentence

denotes

This complex subsequently inhibits calcineurin, which stops the activation of the nuclear factor of activated T cells (NF-AT) that normally causes inflammatory reactions.

T449

57373-57506

Sentence

denotes

The inhibition of NF-AT also leads to lower levels of other factors associated with T helper cell function and thymocyte development.

T450

57507-57550

Sentence

denotes

Cyclosporine was first approved by the U.S.

T451

57551-57819

Sentence

denotes

FDA in 1983 and is orally, parenterally, or topically used to prevent organ transplant rejection, treat/prevent graft-versus-host disease, and treat various inflammatory and autoimmune conditions such as severe rheumatoid arthritis and psoriasis [191,192,193,194,195].

T452

57820-58007

Sentence

denotes

Importantly, low micromolar concentrations of cyclosporin A (<35 µM) substantially impacted the replication of SARS-CoV, human coronavirus 229E, and mouse hepatitis virus in cell culture.

T453

58008-58089

Sentence

denotes

Cyclosporin A significantly inhibited gene expression and reduced progeny titers.

T454

58090-58174

Sentence

denotes

Cyclosporin A treatment completely blocked SARS-CoV RNA and protein synthesis [196].

T455

58175-58346

Sentence

denotes

Cyclosporine A also in vitro reduced the replication of MERS-CoV, transmissible gastroenteritis coronavirus, porcine epidemic diarrhea virus, and feline coronavirus [196].

T456

58347-58421

Sentence

denotes

In fact, cyclosporine A has demonstrated broad-spectrum antiviral effects.

T457

58422-58478

Sentence

denotes

It inhibited the replication of HBV, HCV, and HIV [197].

T458

58479-58724

Sentence

denotes

Cyclosporine also inhibited the replication of Zika virus, West Nile virus, Rift Valley fever virus, and influenza A virus by blocking the interaction of cellular cyclophilins with viral proteins as well as by inhibiting the RNA synthesis [198].

T459

58725-58802

Sentence

denotes

By targeting cyclophilins, the drug can also prevent acute lung injury [199].

T460

58803-59084

Sentence

denotes

Currently, the use of cyclosporin A is being tested in patients with moderate COVID-19 (NCT04412785; n = 20), hospitalized COVID-19 patients (NCT04392531; n = 120), and combined with topical corticosteroid in COVID-19 patients with acute keratoconjunctivitis (NCT04451239; n = 12).

T461

59085-59144

Sentence

denotes

It has also been used in psoriatic COVID-19 patients [200].

T462

59146-59151

Sentence

denotes

4.11.

T463

59152-59175

Sentence

denotes

Deferoxamine (Desferal)

T464

59176-59256

Sentence

denotes

Deferoxamine (Figure S5) is a natural chelating agent from Streptomyces pilosus.

T465

59257-59290

Sentence

denotes

It was first approved by the U.S.

T466

59291-59357

Sentence

denotes

FDA in 1968 and has been parenterally used to treat iron toxicity.

T467

59358-59513

Sentence

denotes

The drug complexes with the ferric ion, primarily in the vascular space, to form ferrioxamine complex that gets subsequently eliminated in urine [201,202].

T468

59514-59595

Sentence

denotes

There are reports about unusually high serum ferritin in COVID-19 patients [203].

T469

59596-59746

Sentence

denotes

A retrospective, multicenter cohort study reported increased levels of serum ferritin in COVID-19 non-survivors compared with COVID-19 survivors [99].

T470

59747-59875

Sentence

denotes

The increase in serum ferritin indicates dysregulated iron homeostasis pertaining to oxidative stress and inflammatory response.

T471

59876-60066

Sentence

denotes

Dysregulated iron homeostasis may propagate the viral infections leading to severe respiratory illnesses such as pulmonary fibrosis and acute respiratory distress syndrome [204,205,206,207].

T472

60067-60188

Sentence

denotes

Accordingly, the use of iron chelators, particularly deferoxamine, in managing/treating COVID-19 has been proposed [208].

T473

60189-60403

Sentence

denotes

Deferoxamine may exert an antiviral effect by depleting iron availability, which has been shown to play a critical role in the replication of RNA viruses such as HCV, HIV, and West Nile virus [209,210,211,212,213].

T474

60404-60510

Sentence

denotes

In addition to its effect on iron level, deferoxamine also appears to have immunomodulatory effects [209].

T475

60511-60628

Sentence

denotes

Along these lines, deferoxamine mitigated the symptoms of Enterovirus-infected mice and decreased the mortality rate.

T476

60629-60718

Sentence

denotes

It also upregulated the B cell levels and improved the neutralizing antibody titer [209].

T477

60719-60866

Sentence

denotes

Deferoxamine has also been reported to in vitro block endothelial inflammation induced by influenza A infection by inhibiting IL-6 synthesis [214].

T478

60867-60915

Sentence

denotes

Deferoxamine may also have antifibrotic effects.

T479

60916-61093

Sentence

denotes

An intranasal treatment with deferoxamine was reported to prevent pulmonary fibrosis and pulmonary functional decline in bleomycin-induced pulmonary fibrosis animal model [206].

T480

61095-61100

Sentence

denotes

4.12.

T481

61101-61120

Sentence

denotes

Atovaquone (Mepron)

T482

61121-61237

Sentence

denotes

Atovaquone is an orally active, synthetic hydroxy-naphthoquinone derivative (Figure S6) with antiparasitic activity.

T483

61238-61265

Sentence

denotes

It was approved by the U.S.

T484

61266-61325

Sentence

denotes

FDA in 1992 against Pneumocystis jirovecii pneumonia [215].

T485

61326-61429

Sentence

denotes

It has also been used to prevent and/or treat toxoplasmosis, malaria, and babesiosis [216,217,218,219].

T486

61430-61620

Sentence

denotes

Mechanistically, it inhibits the electron transport chain in mitochondria, leading to the inhibition of critical metabolic enzymes important for the synthesis of nucleic acids and ATP [220].

T487

61621-61850

Sentence

denotes

It is being evaluated in the U.S. alone (NCT04456153; n = 60) or in combination with azithromycin in an open-label, non-randomized study in COVID-19 patients at HonorHealth Clinical Research Institute, U.S. (NCT04339426; n = 25).

T488

61851-61957

Sentence

denotes

One potential mechanism of action for atovaquone pertaining to SARS-CoV-2 is the inhibition of Mpro [221].

T489

61958-62027

Sentence

denotes

Another computational study suggested that it may inhibit RdRp [169].

T490

62028-62108

Sentence

denotes

Importantly, these computational studies are yet to be experimentally confirmed.

T491

62110-62115

Sentence

denotes

4.13.

T492

62116-62126

Sentence

denotes

Levamisole

T493

62127-62240

Sentence

denotes

It is a tetrahydro-imidazothiazole derivative (Figure S6) that has been used for its immunomodulatory properties.

T494

62241-62284

Sentence

denotes

It was first introduced by Janssen in 1969.

T495

62285-62393

Sentence

denotes

Ever since, it was used as a disease-modifying drug for the treatment of rheumatoid arthritis [222,223,224].

T496

62394-62464

Sentence

denotes

It was also used with 5-fluorouracil for colon cancer treatment [225].

T497

62465-62655

Sentence

denotes

Currently, it is primarily used as an anthelmintic agent for the treatment of ascariasis and hookworm infections owing to its effect on the parasitic nicotinic acetylcholine receptors [226].

T498

62656-62782

Sentence

denotes

It is also used by pediatric nephrologists as a steroid-sparing agent in childhood steroid-dependent nephrotic syndrome [227].

T499

62783-63061

Sentence

denotes

A recent computational exercise has suggested that levamisole potentially binds to the catalytic domain of the viral PLpro, a viral enzyme that processes the newly biosynthesized viral polyproteins and eventually contributes to the maturation and infectivity of the virus [228].

T500

63062-63121

Sentence

denotes

Yet, no experimental validation has been reported thus far.

T501

63122-63293

Sentence

denotes

As of now, orally administered levamisole is being studied alone or in combination with budesonide/formoterol inhaler for the treatment of COVID-19 in few clinical trials.

T502

63294-63370

Sentence

denotes

The rationale for this use has been because of its immunomodulatory effects.

T503

63371-63497

Sentence

denotes

Levamisole acts as an immune-modulator and immune-enhancer by increasing T-cell lymphocyte function and macrophage chemotaxis.

T504

63498-63638

Sentence

denotes

It has also been shown to up-regulate toll-like receptors, stimulate neutrophil chemotaxis, and enhance dendritic cell maturation [229,230].

T505

63639-63749

Sentence

denotes

Furthermore, levamisole attenuated alveolar macrophage dysfunction in respiratory virus-infected calves [231].

T506

63751-63756

Sentence

denotes

4.14.

T507

63757-63765

Sentence

denotes

BLD-2660

T508

63766-63914

Sentence

denotes

It an orally bioavailable, small molecule, reversible covalent inhibitor of calpains, non-lysosomal cysteine proteases, with anti-fibrotic activity.

T509

63915-64086

Sentence

denotes

BLD-2660 exhibited potent and selective inhibition of calpains 1,2, and 9 and thus was found to be efficacious in multiple animal fibrosis models of skin, liver, and lung.

T510

64087-64152

Sentence

denotes

It exhibited high selectivity against related cysteine proteases.

T511

64153-64256

Sentence

denotes

Earlier, several calpain inhibitors were found to reduce the viral replication of SARS-CoV-1 [232,233].

T512

64257-64428

Sentence

denotes

The antiviral activity by calpain inhibition was also verified using siRNA to selectively silence expression of the calpain 2 isoform in SARS-CoV infected cells [232,233].

T513

64429-64548

Sentence

denotes

Undisclosed inhibitors by the developing company were found to reduce SARS-CoV-2 replication in Vero cell-based assays.

T514

64549-64729

Sentence

denotes

Furthermore, in preclinical animal models of lung injury and fibrosis, BLD-2660 was shown to reduce the expression/production of IL-6 in injured lungs and to reduce fibrosis [234].

T515

64730-64988

Sentence

denotes

Owing to the antiviral and anti-inflammatory activities of BLD-2660, it has been advanced to a phase 2, randomized, double-blind, placebo-controlled study to evaluate its safety and antiviral activity in COVID-19 hospitalized subjects (NCT04334460; n = 120).

T516

64990-64995

Sentence

denotes

4.15.

T517

64996-65024

Sentence

denotes

N-Acetylcysteine (Acetadote)

T518

65025-65122

Sentence

denotes

It is a small molecule in which the amino group of cysteine amino acid is acetylated (Figure S6).

T519

65123-65164

Sentence

denotes

N-acetylcysteine was approved by the U.S.

T520

65165-65270

Sentence

denotes

FDA in 1963 for the oral use as mucolytic agent and parenteral use to treat acetaminophen overdose [235].

T521

65271-65367

Sentence

denotes

Currently, there are about six ongoing clinical trials to evaluate its use in COVID-19 patients.

T522

65368-65484

Sentence

denotes

The rationale for these studies is attributed to its potential antiviral, antioxidant, and immunomodulatory effects.

T523

65485-65625

Sentence

denotes

In this arena, several experiments have shown that acetylcysteine may eventually inhibit the viral replication of influenza A [236,237,238].

T524

65626-65729

Sentence

denotes

Acetylcysteine has also been evaluated for use in the treatment of HIV in two randomized studies [239].

T525

65730-65938

Sentence

denotes

Although its effect on the viral load was not consistent, the two studies consistently demonstrated that acetylcysteine substantially increased immunological functions and plasma albumin concentrations [239].

T526

65939-66140

Sentence

denotes

Furthermore, its free sulfhydryl group cleaves the disulfide bonds in mucoproteins which lowers mucous viscosity in patients with cystic fibrosis or chronic obstructive pulmonary disease [240,241,242].

T527

66141-66282

Sentence

denotes

At higher doses, acetylcysteine can also be used as an antioxidant to mitigate the symptoms of many diseases complicated by oxidative stress.

T528

66283-66423

Sentence

denotes

In fact, as a component in the synthesis of the antioxidant glutathione, it may reduce the formation of proinflammatory cytokines [243,244].

T529

66424-66582

Sentence

denotes

Acetylcysteine has also been found to mitigate the oxidative stress and improve the inflammatory response in patients with community acquired pneumonia [245].

T530

66584-66589

Sentence

denotes

4.16.

T531

66590-66600

Sentence

denotes

Artesunate

T532

66601-66673

Sentence

denotes

It is a polycyclic natural product with endoperoxide moiety (Figure S6).

T533

66674-66715

Sentence

denotes

It is parenterally used to treat malaria.

T534

66716-66850

Sentence

denotes

Initially, there was not enough information about its efficacy against SARS-CoV, except the results of herbal extract screening [246].

T535

66851-67038

Sentence

denotes

It is now being evaluated in few clinical trials alone (NCT04387240; n = 22) or in combination with pyronaridine, another antimalarial drug (NCT04475107; n = 76 and NCT04532931; n = 250).

T536

67039-67184

Sentence

denotes

In particular, the combination exhibited antiviral activity against SARS-CoV-2 and influenza viruses in human lung epithelial Calu-3 cells [247].

T537

67185-67358

Sentence

denotes

Other artemisinin-based combinations that appear to be on the rise for potentially treating COVID-19 are mefloquine-artesunate [248] and arteannuin B and lumefantrine [249].

T538

67360-67365

Sentence

denotes

4.17.

T539

67366-67401

Sentence

denotes

Povidone-Iodine Solution (Betadine)

T540

67402-67491

Sentence

denotes

Povidone-iodine is a chemical complex of polyvinylpyrrolidone polymer and iodine (PVP-I).

T541

67492-67668

Sentence

denotes

It is being tested in the U.S., France, United Kingdom, Singapore, and Malaysia as a gargle, mouthwash, or nasal spray to reduce nasopharyngeal viral load in COVID-19 patients.

T542

67669-67846

Sentence

denotes

Reports have highlighted the virucidal effect of diluted PVP-I concentration (<10%), without toxic effects on respiratory cilia, olfactory function, or mucosal appearance [250].

T543

67847-68172

Sentence

denotes

In this direction, in vitro studies of 0.23% PVP-I mouthwash suggested that, following a 15-s exposure, the solution can provide effective antiviral activity against influenza virus A (H1N1), MERS-CoV, rotavirus, and SARS-CoV as well as antibacterial activity against Klebsiella pneumoniae and Streptococcus pneumoniae [251].

T544

68174-68179

Sentence

denotes

4.18.

T545

68180-68203

Sentence

denotes

Chlorhexidine (Peridex)

T546

68204-68326

Sentence

denotes

Chlorhexidine is a broad-spectrum, guanidino-containing antimicrobial agent (Figure S6) that is widely used as antiseptic.

T547

68327-68414

Sentence

denotes

It was first approved in the U.S. in 1986 and is used for gingivitis and periodontitis.

T548

68415-68541

Sentence

denotes

It is also used for the oropharyngeal sanitization to reduce the risk of ventilator-associated or hospital-acquired pneumonia.

T549

68542-68610

Sentence

denotes

It is used as a skin disinfectant for preoperative skin preparation.

T550

68611-68762

Sentence

denotes

It can also be used to disinfect hands, surface wounds, surgical tools, and surgical scrub, for both patients and healthcare workers [252,253,254,255].

T551

68763-68866

Sentence

denotes

Mechanistically, it has both micro-biostatic and micro-biocidal effects depending on its concentration.

T552

68867-69109

Sentence

denotes

The former effect happens at low concentrations due to the binding of this cationic molecule to the negatively charged extracellular components of some microbes, which causes an alteration of osmotic equilibrium and leakage of essential ions.

T553

69110-69267

Sentence

denotes

At higher concentrations, the molecule gets into the microbial cells and precipitates intracellular components, leading to microbial death [252,253,254,255].

T554

69268-69512

Sentence

denotes

Currently, 0.12% chlorhexidine oral/nasal rinse is being tested in a randomized, open-label, single-institution study so as to evaluate its potential to reduce oro- and naso-pharyngeal viral load in patients with COVID-19 (NCT04344236; n = 48).

T555

69513-69691

Sentence

denotes

Recently, computational methods have proposed chlorhexidine to be an inhibitor of 3CLpro and/or RdRp of SARS-CoV-2 [169], yet this potential is to be experimentally demonstrated.

T556

69693-69698

Sentence

denotes

4.19.

T557

69699-69726

Sentence

denotes

Methylene Blue (ProvayBlue)

T558

69727-69825

Sentence

denotes

Methylene blue is disubstituted phenothiazine derivative (Figure S6) that was approved by the U.S.

T559

69826-69880

Sentence

denotes

FDA for the parenteral treatment of methemoglobinemia.

T560

69881-69940

Sentence

denotes

It acts by forming leukomethylene blue complex within RBCs.

T561

69941-70038

Sentence

denotes

The product is a reducing agent that converts the ferric ion back to the ferrous ion state [256].

T562

70039-70103

Sentence

denotes

Methylene blue has antiviral activity [257,258,259,260,261,262].

T563

70104-70285

Sentence

denotes

A recent study showed that photochemical treatment in conjunction with methylene blue can be used to inactivate SARS-CoV-2 for blood safety and in convalescent plasma therapy [257].

T564

70286-70438

Sentence

denotes

Methylene blue is also known to kill coronavirus (specifically SARS-CoV-2) and HIV in the blood supply when combined with photo-biomodulation [258,259].

T565

70439-70680

Sentence

denotes

Methylene blue and UV/visible light have also been reported to inactivate different viruses, in plasma and in platelet concentrates, including SARS-CoV, MERS-CoV, Ebola virus, Crimean-Congo hemorrhagic fever virus, and Nipah virus [260,261].

T566

70681-70807

Sentence

denotes

A mice model study also demonstrated the ability of methylene blue plus fluorescent light to inactivate West Nile Virus [262].

T567

70808-70856

Sentence

denotes

It is also effective against septic shock [263].

T568

70857-71016

Sentence

denotes

Furthermore, methylene blue is a potent inhibitor of guanylate cyclase, and thus, it improves the arterial pressure and cardiac function in septic shock [264].

T569

71017-71153

Sentence

denotes

It also improves systemic vascular resistance and mean arterial pressure while decreases vasopressor requirements in septic shock [265].

T570

71154-71260

Sentence

denotes

It also demonstrates anti-inflammatory effects because it can inhibit NLRP3 inflammasome activation [266].

T571

71261-71443

Sentence

denotes

The drug is currently being tested in the context of COVID-19 in a few trials alone (NCT04376788; n = 15) or in combination with vitamin C and N-acetylcysteine (NCT04370288; n = 20).

T572

71445-71450

Sentence

denotes

4.20.

T573

71451-71471

Sentence

denotes

Inhaled Nitric Oxide

T574

71472-71572

Sentence

denotes

Nitric oxide is an endogenous signaling molecule that is involved in a host of biological processes.

T575

71573-71701

Sentence

denotes

The molecule is produced internally by the action of nitric oxide synthase enzyme that catalyzes its production from L-arginine.

T576

71702-71954

Sentence

denotes

The antimicrobial activity of nitric oxide has been described against several protozoal and bacterial pathogens as well as against some viruses (herpes simplex virus 1, neurotropic murine coronavirus, and murine hepatitis virus strain 3) [267,268,269].

T577

71955-72109

Sentence

denotes

The role of nitric oxide in SARS-CoV infection was earlier investigated in Vero E6 cells by using the nitric oxide donor S-nitroso-N-acetyl-penicillamine.

T578

72110-72257

Sentence

denotes

The study revealed that the nitric oxide donor substantially inhibited the replication of SARS-CoV in a concentration-dependent fashion (0–400 µM).

T579

72258-72317

Sentence

denotes

Nitric oxide inhibited the viral protein and RNA synthesis.

T580

72318-72460

Sentence

denotes

Importantly, the study demonstrated that nitric oxide produced by inducible nitric oxide synthase inhibited the replication of SARS-CoV [270].

T581

72461-72572

Sentence

denotes

Another study revealed that nitric oxide causes a reduction in the palmitoylation of the viral spike S protein.

T582

72573-72662

Sentence

denotes

This subsequently impedes the fusion between the viral spike S protein and the host ACE2.

T583

72663-72793

Sentence

denotes

Moreover, nitric oxide also leads to a substantial decrease in viral RNA production in the early steps of viral replication [271].

T584

72794-72893

Sentence

denotes

These outcomes were attributed to its potential effect on the cysteine proteases of SARS-CoV [272].

T585

72894-73069

Sentence

denotes

Given that the genome of SARS-CoV is significantly similar to SARS-CoV-2, the inhaled nitric oxide therapy in COVID-19 patients is predicted to produce the same effects [273].

T586

73070-73218

Sentence

denotes

Nitric oxide is also a vasodilator; thus, it has been found to promote a selective bronchodilatory effect, which may also benefit COVID-19 patients.

T587

73219-73279

Sentence

denotes

The vasodilation is mediated by activating guanylyl cyclase.

T588

73280-73445

Sentence

denotes

In fact, the administration of inhaled nitric oxide to critically ill patients of SARS-CoV was found to reverse pulmonary hypertension and to improve severe hypoxia.

T589

73446-73534

Sentence

denotes

Nitric oxide administration also shortened the time needed of ventilation support [274].

T590

73535-73726

Sentence

denotes

Along these lines, a positive result was recently reported for inhaled nitric oxide in an outpatient with COVID-19 infection and vasoreactive idiopathic pulmonary arterial hypertension [275].

T591

73727-73854

Sentence

denotes

Currently, there are about 17 clinical trials being performed to evaluate the use of inhaled nitric oxide in COVID-19 patients.

T592

73855-74150

Sentence

denotes

Other forms to indirectly deliver nitric oxide include the intravenous administration of nitrite oxide (NCT04401527; n = 200) or the nasal delivery of GLS-1200 which contains quinine diluted in saline and has been reported to stimulate nasal cells to produce nitric oxide (NCT04408183; n = 225).

T593

74152-74157

Sentence

denotes

4.21.

T594

74158-74172

Sentence

denotes

Poly-Alcohols:

T595

74173-74198

Sentence

denotes

Resveratrol and Quercetin

T596

74199-74285

Sentence

denotes

On the one hand, resveratrol is a natural polyphenolic stilbene derivative (Figure 9).

T597

74286-74435

Sentence

denotes

Resveratrol exhibits several biological activities, including antioxidant, antitumor, anti-inflammatory, oxygen scavenging, and antiviral activities.

T598

74436-74516

Sentence

denotes

Resveratrol inhibits TNF-induced activation of NF-κB in a dose-dependent manner.

T599

74517-74586

Sentence

denotes

Furthermore, it inhibits cyclooxygenase and hydro-peroxidase enzymes.

T600

74587-74711

Sentence

denotes

Not only that but it also inhibits vascular cell adhesion molecule expression and vascular smooth muscle cell proliferation.

T601

74712-74843

Sentence

denotes

It also stimulates endothelial nitric oxide synthase activity and inhibits platelet aggregation and LDL peroxidation [276,277,278].

T602

74844-74930

Sentence

denotes

All these effects are expected to help fight COVID-19 infection and its complications.

T603

74931-75056

Sentence

denotes

Importantly, resveratrol significantly inhibited MERS-CoV replication in vitro mainly by inhibiting the RNA production [279].

T604

75057-75159

Sentence

denotes

Resveratrol also inhibited the replication of duck enteritis virus [280] and pseudorabies virus [281].

T605

75160-75345

Sentence

denotes

Accordingly, the safety and efficacy of resveratrol in COVID-19 patients are being tested in a randomized double-blind, placebo-controlled proof-of-concept trial (NCT04400890; n = 200).

T606

75346-75428

Sentence

denotes

On the other hand, quercetin is a natural penta-hydroxylated flavonoid (Figure 9).

T607

75429-75553

Sentence

denotes

Similar to resveratrol, quercetin possesses antioxidant, oxygen scavenging, anti-inflammatory, and cardioprotective effects.

T608

75554-75672

Sentence

denotes

Quercetin also inhibits platelet aggregation and lipid peroxidation and affects the function of several kinases [282].

T609

75673-75773

Sentence

denotes

Importantly, quercetin also exhibits a wide spectrum antiviral activity against DNA and RNA viruses.

T610

75774-75853

Sentence

denotes

For example, quercetin inhibited several respiratory viruses in cultured cells.

T611

75854-75974

Sentence

denotes

It also inhibited the cytopathic effects of rhinoviruses, echoviruses, coxsackieviruses, and polioviruses [283,284,285].

T612

75975-76128

Sentence

denotes

Quercetin also significantly reduced plaque formation by polio virus, herpes simplex virus 1, respiratory syncytial virus, and parainfluenza virus [286].

T613

76129-76222

Sentence

denotes

Furthermore, quercetin inhibited the replication of cytomegalovirus and dengue virus 2 [287].

T614

76223-76390

Sentence

denotes

The antiviral effects of quercetin are thought to be because it either blocks the virus entry or inhibits the viral replication enzymes, i.e., viral polymerases [288].

T615

76391-76474

Sentence

denotes

Other flavonoids have recently been reported as potential inhibitors of Mpro [289].

T616

76475-76609

Sentence

denotes

Accordingly, the effect of quercetin alone as a prophylactic or as a treatment is being tested in COVID-19 patients (NCT04377789; 50).

T617

76610-76692

Sentence

denotes

It is also being tested with zinc, bromelain, and vitamin C (NCT04468139; n = 60).

T618

76694-76699

Sentence

denotes

4.22.

T619

76700-76715

Sentence

denotes

Macromolecules:

T620

76716-76759

Sentence

denotes

Thymalfasin, Lactoferrin, TY027, and XAV-19

T621

76760-76912

Sentence

denotes

Thymalfasin (thymosin-α1, Zadaxin) is a 28-amino acid synthetic peptide that is identical to the natural thymosin-α1 produced by the thymus gland [290].

T622

76913-77040

Sentence

denotes

It possesses immunoregulatory properties owing primarily to its ability to activate various immune cells, particularly T cells.

T623

77041-77170

Sentence

denotes

It is used alone or in combination with INFs as an immunomodulator for the treatment of chronic HBV and HCV infections [291,292].

T624

77171-77333

Sentence

denotes

Thymalfasin can also be used for the treatment of chemotherapy-induced immune suppression, and to increase the efficacy of HBV and influenza virus vaccines [293].

T625

77334-77414

Sentence

denotes

Currently, it is being tested in few clinical trials in the context of COVID-19.

T626

77415-77535

Sentence

denotes

An important study is the trial to prevent COVID-19 infection in elderly renal dialysis patients (NCT04428008; n = 240).

T627

77536-77625

Sentence

denotes

Lactoferrin is another macromolecule that is being considered in the context of COVID-19.

T628

77626-77766

Sentence

denotes

It is an iron-binding, multifunctional globular glycoprotein that is widely present in secretory biological fluids, particularly milk [294].

T629

77767-77876

Sentence

denotes

Lactoferrin exhibits a broad-spectrum antimicrobial activity against bacterial, viral, and fungal infections.

T630

77877-78030

Sentence

denotes

It also appears to exhibit a clinically relevant activity against some forms of cancer [295], cystic fibrosis [296], and necrotizing enterocolitis [297].

T631

78031-78288

Sentence

denotes

Literature indicates that lactoferrin exhibits activity against a wide range of RNA and DNA viruses, including cytomegalovirus, herpes simplex viruses, HIV, HCV, poliovirus, hantaviruses, rotaviruses, human respiratory syncytial virus, and others [298,299].

T632

78289-78364

Sentence

denotes

Importantly, lactoferrin also appears to exhibit activity against SARS-CoV.

T633

78365-78449

Sentence

denotes

It was shown that lactoferrin prevented SARS-CoV from entering human cultured cells.

T634

78450-78672

Sentence

denotes

Lactoferrin appeared to block the interaction between the viral spike S protein and heparan sulfate proteoglycans, which serve as an anchoring site on the host cell surface during the early phase of virus infections [300].

T635

78673-78841

Sentence

denotes

Lactoferrin was also found to support the growth of the gut flora as well as the enterocytes proliferation with direct anti-inflammatory/immunomodulatory effects [301].

T636

78842-79068

Sentence

denotes

Currently, lactoferrin is being tested in few clinical trials for COVID-19, including liposomal lactoferrin in COVID-19 patients with mild-to-moderate disease as well as in asymptomatic COVID-19 patients (NCT04475120; n = 60).

T637

79069-79340

Sentence

denotes

Other antiviral macromolecules that are being tested against COVID-19 include TY027, a monoclonal antibody (NCT04429529; n = 25), and XAV-19, a heterologous swine glyco-humanized polyclonal antibody raised against the spike S protein of SARS-CoV-2 (NCT04453384; n = 368).

T638

79341-79481

Sentence

denotes

Lastly, other strategies are being clinically evaluated to treat COVID-19 patients as they may produce direct or indirect antiviral effects.

T639

79482-79786

Sentence

denotes

These include the use of convalescent plasma (hyperimmune plasma) from fully recovered individuals [302], immunoglobulins, INFs (such as INF β-1a, INF β-1b, pegylated INF γ-1a and others) [303,304], RNA virus-based gene vector (such as DeltaRex-G) (NCT04378244; n = 18), and mesenchymal stem cells [305].

T640

79787-80051

Sentence

denotes

Furthermore, several anti-inflammatory/immune-modulatory drugs, antithrombotic drugs, and vitamins (vitamins C and D) are also being tested to prevent and/or treat severe COVID-19 cases that may arise because of excessive inflammation and thrombotic complications.

T641

80052-80139

Sentence

denotes

Most frequently tested anti-inflammatory/immunomodulatory agents are listed in Table 2.

T642

80140-80268

Sentence

denotes

Antithrombotic agents that are most frequently being tested in clinical trials for COVID-19 patients are also listed in Table 3.

T643

80270-80272

Sentence

denotes

5.

T644

80273-80284

Sentence

denotes

Conclusions

T645

80285-80345

Sentence

denotes

The life cycle of SARS-CoV-2 can be divided into two phases.

T646

80346-80455

Sentence

denotes

On the one hand, events prior to the viral RNA replication represent the early stage of the virus life cycle.

T647

80456-80682

Sentence

denotes

This stage involves the binding of the virus to the host cell receptor, its membrane fusion with the host cell membrane, clathrin-mediated endocytosis, and the release of the viral genome into the host cytoplasmic environment.

T648

80683-80813

Sentence

denotes

On the other hand, events that involve RNA replication and subsequent processes represent the later stage of the virus life cycle.

T649

80814-80962

Sentence

denotes

Specifically, it entails the RNA replication process, viral protein synthesis and processing, and viral particle assembly, and mature virus release.

T650

80963-81072

Sentence

denotes

Notably, events in the two phases are mediated by several interactions among various viral and host proteins.

T651

81073-81206

Sentence

denotes

For example, the viral entry is initially mediated by interactions between the viral spike S protein and the host cell receptor ACE2.

T652

81207-81309

Sentence

denotes

Furin, TMPRSS2, and cathepsin L enzymes are also important for the early stage of the viral infection.

T653

81310-81463

Sentence

denotes

Importantly, the later stage of the viral life cycle involves a different set of virus–host interactions that are mediated by a different set of enzymes.

T654

81464-81704

Sentence

denotes

For example, the virus genetic material replication is catalyzed by RdRp and requires nucleotides that are provided by the host cell and biosynthesized by enzymes such as inosine monophosphate dehydrogenase and dihydroorotate dehydrogenase.

T655

81705-81827

Sentence

denotes

Furthermore, the resulting viral proteins require further processing which takes place by the action of by Mpro and PLpro.

T656

81828-82003

Sentence

denotes

Importantly, any of the virus or the host proteins and the associated events can serve as a potential drug target for the design and development of anti-COVID-19 therapeutics.

T657

82004-82121

Sentence

denotes

We previously reviewed potential anti-COVID-19 therapeutics that target the early stage in the viral life cycle [12].

T658

82122-82236

Sentence

denotes

In this review, we summarized potential therapeutics that interfere with the post-entry events of the viral cycle.

T659

82237-82404

Sentence

denotes

Important molecular targets to be considered here are the viral RNA polymerase, the viral processing Mpro and PLpro enzymes, and the host dihydroorotate dehydrogenase.

T660

82405-82504

Sentence

denotes

In this arena, we described potential therapeutics that are currently listed in clinicaltrials.gov.

T661

82505-83091

Sentence

denotes

These include small molecule drugs such as nucleoside-based antivirals (galidesivir, ribavirin, clevudine, emtricitabine, and EIDD-2801), nucleotide-based antivirals, (remdesivir, tenofovir, and AT-527), arylpropanol-based peptidomimetics (lopinavir, ritonavir, and others), NSAIDs (indomethacin and naproxen), inhaled nitric oxide, polyalcohol natural products (resveratrol and quercetin), antiprotozoal and antimalarial drugs (nitazoxanide, levamisole, atovaquone, and artesunate), cyclic and acyclic natural peptides (deferoxamine, plitidepsin, and cyclosporine A), and a few others.

T662

83092-83272

Sentence

denotes

The case of favipiravir is also unique as it is a non-nucleoside(tide) drug, yet it gets subsequently activated to the corresponding active form of favipiravir-ribose-triphosphate.

T663

83273-83380

Sentence

denotes

The described therapeutics also include macromolecules such as thymalfasin, lactoferrin, TY027, and XAV-19.

T664

83381-83516

Sentence

denotes

Many of the above drugs are currently approved therapeutics for other indications; thus, they present a unique repurposing opportunity.

T665

83517-83628

Sentence

denotes

Yet, others are new molecular entities such as AR-527, EIDD-2801, ACS-09, vidofludimus, VERU-111, and BLD-2660.

T666

83629-83801

Sentence

denotes

Interestingly, the reviewed therapeutics exploit a range of mechanisms which will essentially enhance the likelihood of obtaining effective therapeutics in a timely manner.

T667

83802-83911

Sentence

denotes

Furthermore, many of the presented therapeutics promote pharmacological effects beyond the antiviral effects.

T668

83912-84030

Sentence

denotes

Of note are the anti-inflammatory/immune-modulatory effects of selinexor, NSAIDs, VERU-111, leflunomide, and BLD-2660.

T669

84031-84150

Sentence

denotes

These effects are of enormous significance due to the confirmed excessive inflammation in the severe cases of COVID-19.

T670

84151-84372

Sentence

denotes

It is worth mentioning here that testing of the described therapeutics in COVID-19 clinical trials is based on either initial clinical observations or reported activity against previous outbreaks of SARS-CoV and MERS-CoV.

T671

84373-84663

Sentence

denotes

Lastly, although the individual use of the described therapeutics can be beneficial, yet a combination of the above drugs with each other and/or with those that impact the early stage of the viral life cycle will likely lead to a higher success rate in treating the critically ill patients.

T672

84664-84849

Sentence

denotes

The clinical outcome is likely to be further improved by the addition of immune-therapeutics and anticoagulants to address the issues of cytokine storm and coagulopathies, respectively.

T673

84850-84981

Sentence

denotes

Based on initial results, remdesivir, favipiravir, EIDD-2801, and selinexor appear to carry the most promising therapeutic effects.

T674

84982-85015

Sentence

denotes

In fact, on May 1, 2020, the U.S.

T675

85016-85202

Sentence

denotes

FDA issued an emergency use authorization for remdesivir to be distributed and used by licensed health care providers to treat adults and children hospitalized with severe COVID-19 [25].

T676

85203-85365

Sentence

denotes

On May 30, 2020, the Russian Health Ministry approved a generic version of favipiravir named avifavir for the treatment of COVID-19 in the hospital settings [10].

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