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Id Subject Object Predicate Lexical cue
T1 0-97 Sentence denotes Potential Anti-SARS-CoV-2 Therapeutics That Target the Post-Entry Stages of the Viral Life Cycle:
T2 98-120 Sentence denotes A Comprehensive Review
T3 122-130 Sentence denotes Abstract
T4 131-240 Sentence denotes The coronavirus disease-2019 (COVID-19) pandemic continues to challenge health care systems around the world.
T5 241-385 Sentence denotes Scientists and pharmaceutical companies have promptly responded by advancing potential therapeutics into clinical trials at an exponential rate.
T6 386-468 Sentence denotes Initial encouraging results have been realized using remdesivir and dexamethasone.
T7 469-710 Sentence denotes Yet, the research continues so as to identify better clinically relevant therapeutics that act either as prophylactics to prevent the infection or as treatments to limit the severity of COVID-19 and substantially decrease the mortality rate.
T8 711-832 Sentence denotes Previously, we reviewed the potential therapeutics in clinical trials that block the early stage of the viral life cycle.
T9 833-964 Sentence denotes In this review, we summarize potential anti-COVID-19 therapeutics that block/inhibit the post-entry stages of the viral life cycle.
T10 965-1191 Sentence denotes The review presents not only the chemical structures and mechanisms of the potential therapeutics under clinical investigation, i.e., listed in clinicaltrials.gov, but it also describes the relevant results of clinical trials.
T11 1192-1261 Sentence denotes Their anti-inflammatory/immune-modulatory effects are also described.
T12 1262-1353 Sentence denotes The reviewed therapeutics include small molecules, polypeptides, and monoclonal antibodies.
T13 1354-1491 Sentence denotes At the molecular level, the therapeutics target viral proteins or processes that facilitate the post-entry stages of the viral infection.
T14 1492-1645 Sentence denotes Frequent targets are the viral RNA-dependent RNA polymerase (RdRp) and the viral proteases such as papain-like protease (PLpro) and main protease (Mpro).
T15 1646-1798 Sentence denotes Overall, we aim at presenting up-to-date details of anti-COVID-19 therapeutics so as to catalyze their potential effective use in fighting the pandemic.
T16 1800-1802 Sentence denotes 1.
T17 1803-1815 Sentence denotes Introduction
T18 1816-2098 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 2099-2359 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 2360-2528 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 2529-2664 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 2665-2760 Sentence denotes Efforts are ongoing to deliver an effective vaccine to protect individuals against the disease.
T23 2761-2911 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 2912-3331 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 3332-3488 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 3489-3609 Sentence denotes Furthermore, favipiravir has been approved for the treatment of COVID-19 in the hospital settings in few countries [10].
T27 3610-3778 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 3779-3886 Sentence denotes Despite the above recommendations and/or approvals, the need for effective treatment remains largely unmet.
T29 3887-4015 Sentence denotes Therefore, a large number of potential therapeutics continue to be developed and others are being advanced into clinical trials.
T30 4016-4149 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 4150-4331 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 4332-4404 Sentence denotes We only include those therapeutics that are listed in clinicatrials.gov.
T33 4405-4460 Sentence denotes They include both old drugs and new molecular entities.
T34 4461-4543 Sentence denotes Many of the potential therapeutics are small molecules and few are macromolecules.
T35 4544-4610 Sentence denotes Some of these therapeutics also possess anti-inflammatory effects.
T36 4612-4683 Sentence denotes The Life Cycle of SARS-COV-2 and Potential Targets for Drug Development
T37 4684-4777 Sentence denotes The life cycle of the virus includes early-stage events and later-stage events (Figure 1a,b).
T38 4778-4923 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 4924-5188 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 5189-5288 Sentence denotes Alternatively, the bound virus spike S protein can also be proteolytically activated by furin [16].
T41 5289-5487 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 5488-5708 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 5709-5889 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 5890-6208 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 6209-6349 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 6350-6443 Sentence denotes The viral RdRp is also responsible for the replication and amplification of the viral genome.
T47 6444-6694 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 6695-6866 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 6867-7016 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 7017-7178 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 7179-7326 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 7327-7495 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 7496-7674 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 7676-7678 Sentence denotes 2.
T55 7679-7706 Sentence denotes Viral Polymerase Inhibitors
T56 7708-7712 Sentence denotes 2.1.
T57 7713-7742 Sentence denotes Remdesivir (Veklury, GS-5734)
T58 7743-7845 Sentence denotes Remdesivir is an adenosine monophosphate derivative and nucleotide-based antiviral prodrug (Figure 2).
T59 7846-7924 Sentence denotes Remdesivir received, in May 2020, an emergency use authorization from the U.S.
T60 7925-8062 Sentence denotes FDA for the treatment of laboratory-confirmed or suspected COVID-19 illness in children and adults hospitalized with severe disease [25].
T61 8063-8190 Sentence denotes The parenterally administered drug is being developed by Gilead Sciences, U.S., and has broad-spectrum antiviral activity [26].
T62 8191-8266 Sentence denotes It was first studied in 2016 as a potential treatment for Ebola virus [27].
T63 8267-8435 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 8436-8573 Sentence denotes The drug is metabolized to the pharmacologically active nucleoside triphosphate metabolite after being distributed into cells (Figure 2).
T65 8574-8746 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 8747-8843 Sentence denotes The termination is delayed and happens after the addition of more nucleotides (between 3 and 5).
T67 8844-8952 Sentence denotes Therefore, remdesivir is described as a direct antiviral agent acting as a delayed chain terminator [30,31].
T68 8953-9030 Sentence denotes Importantly, remdesivir avoids proofreading by viral exoribonuclease [28,32].
T69 9031-9146 Sentence denotes Currently, remdesivir is being evaluated as a treatment for COVID-19 patients in about 15 studies across the globe.
T70 9147-9328 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 9329-9440 Sentence denotes In particular, merimepodib is another antiviral agent that is inhibitor of inosine monophosphate dehydrogenase.
T72 9441-9505 Sentence denotes The enzyme is required for the synthesis of guanine nucleotides.
T73 9506-9621 Sentence denotes Merimepodib consequently inhibits the synthesis of DNA and RNA, leading to antiviral and immunosuppressive effects.
T74 9622-9726 Sentence denotes Thus, remdesivir and merimepodib is a dual-acting antiviral combination with immunosuppressive activity.
T75 9727-9874 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 9875-10072 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 10073-10275 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 10276-10504 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 10505-10644 Sentence denotes Furthermore, remdesivir with interferon (INF)-b demonstrated better antiviral activity compared to lopinavir/ritonavir with INF-b in vitro.
T80 10645-10861 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 10862-11006 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 11007-11164 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 11165-11362 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 11363-11716 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 11717-11776 Sentence denotes The mortality rate was also similar in the two groups [37].
T86 11777-11840 Sentence denotes Yet, the trial was criticized for being insufficiently powered.
T87 11841-12119 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 12120-12212 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 12213-12344 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 12345-12503 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 12504-12605 Sentence denotes Similar results were obtained in hospitalized adults (n = 1600) with moderate COVID-19 (NCT04292730).
T92 12606-12748 Sentence denotes In an uncontrolled study of hospitalized COVID-19 patients (n = 61), most patients needed less oxygen support after receiving remdesivir [39].
T93 12749-12840 Sentence denotes Importantly, a phase 3 adaptive, randomized, placebo-controlled study sponsored by the U.S.
T94 12841-13206 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 13207-13269 Sentence denotes As of now, the COVID-19 Treatment Guidelines Panel of the U.S.
T96 13270-13496 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 13497-13661 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 13662-13679 Sentence denotes Of note, the U.S.
T99 13680-13884 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 13885-14062 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 14064-14068 Sentence denotes 2.2.
T102 14069-14104 Sentence denotes Galidesivir (Immucillin-A, BCX4430)
T103 14105-14218 Sentence denotes Galidesivir is an adenosine nucleoside analog (Figure 3) that is an active site inhibitor of RdRp (EC50 < 50 µM).
T104 14219-14358 Sentence denotes Similar to remdesivir, it is a prodrug that is metabolized by cellular kinases to the corresponding active form of nucleoside triphosphate.
T105 14359-14522 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 14523-14684 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 14685-14728 Sentence denotes NIAID (NCT03891420; n = 132) [44,45,46,47].
T108 14729-14928 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 14929-15080 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 15082-15086 Sentence denotes 2.3.
T111 15087-15107 Sentence denotes Ribavirin (Virazole)
T112 15108-15198 Sentence denotes It is an open-ring analog of guanosine nucleoside (Figure 3) that was approved by the U.S.
T113 15199-15265 Sentence denotes FDA in 1985 for the treatment of respiratory syncytial virus [48].
T114 15266-15379 Sentence denotes It is also used systemically for chronic hepatitis C virus (HCV) infection [49] and viral hemorrhagic fever [50].
T115 15380-15466 Sentence denotes The drug possesses broad-spectrum antiviral activity against both RNA and DNA viruses.
T116 15467-15658 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 15659-15756 Sentence denotes Other mechanisms have also been proposed to account for its broad spectrum of antiviral activity.
T118 15757-15959 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 15960-16070 Sentence denotes Decreased intracellular GTP pool decreases viral protein synthesis and limits the replication of viral genome.
T120 16071-16177 Sentence denotes Ribavirin is also a mutagen that leads to defective virions [52] and it has immunomodulatory actions [53].
T121 16178-16310 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 16311-16403 Sentence denotes Ribavirin is currently being evaluated in few trials for the treatment of COVID-19 patients.
T123 16404-16589 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 16590-16693 Sentence denotes Recent computational work has shown that ribavirin binds with high affinity to RdRp of SARS-CoV-2 [55].
T125 16694-16800 Sentence denotes Furthermore, the MERS-CoV rhesus macaque model revealed promising results for ribavirin and IFN-α 2b [56].
T126 16801-16937 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 16938-17159 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 17160-17542 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 17544-17548 Sentence denotes 2.4.
T130 17549-17580 Sentence denotes Clevudine (Levovir and Revovir)
T131 17581-17712 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 17713-17849 Sentence denotes Similar to previous agents, it is a prodrug that requires phosphorylation to form the corresponding active nucleotide, the triphosphate.
T133 17850-18001 Sentence denotes Mechanistically, the triphosphate active form appears to noncompetitively inhibit the HBV reverse transcriptase protein priming and DNA synthesis [61].
T134 18002-18170 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 18171-18271 Sentence denotes The drug is being evaluated in a phase 2 as a treatment for COVID-19 in Korea (NCT04347915; n = 60).
T136 18273-18277 Sentence denotes 2.5.
T137 18278-18367 Sentence denotes Emtricitabine (Emtriva) in Combination with Tenofovir Disoproxil or Tenofovir Alafenamide
T138 18368-18521 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 18522-18610 Sentence denotes It is metabolized by cellular kinases-mediated phosphorylation to the triphosphate form.
T140 18611-18838 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 18839-18878 Sentence denotes The drug was first approved by the U.S.
T142 18879-18949 Sentence denotes FDA as an orally bioavailable, once-daily antiretroviral drug in 2003.
T143 18950-19057 Sentence denotes It is now used in combination with other antiretroviral drugs for the treatment of HIV-1 infection [62,63].
T144 19058-19284 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 19285-19543 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 19544-19868 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 19869-19910 Sentence denotes It was first approved in 2001 by the U.S.
T148 19911-19997 Sentence denotes FDA and is prescribed for the oral treatment of HIV-1 and chronic HBV infections [65].
T149 19998-20181 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 20182-20460 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 20461-20633 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 20634-20850 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 20851-21029 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 21030-21246 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 21247-21328 Sentence denotes It also decreases the potential renal toxicity of the monophosphate intermediate.
T156 21329-21389 Sentence denotes Tenofovir alafenamide was first approved in 2016 by the U.S.
T157 21390-21457 Sentence denotes FDA and is prescribed for the oral treatment of HBV infection [68].
T158 21458-21696 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 21697-21986 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 21988-21992 Sentence denotes 2.6.
T161 21993-22020 Sentence denotes Favipiravir (Avigan, T-705)
T162 22021-22083 Sentence denotes Favipiravir was originally developed by Fujifilm group, Japan.
T163 22084-22176 Sentence denotes It is a pyrazine-carboxamide derivative (Figure 4) with a broad-spectrum antiviral activity.
T164 22177-22243 Sentence denotes It selectively and potently inhibits the RdRp of RNA viruses [69].
T165 22244-22320 Sentence denotes Favipiravir is a prodrug that requires bioactivation in host-infected cells.
T166 22321-22375 Sentence denotes Its active form is favipiravir-ribose-5′-triphosphate.
T167 22376-22587 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 22588-22754 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 22755-22894 Sentence denotes Favipiravir is effective against several strains of influenza viruses, including those that are resistant to existing anti-influenza drugs.
T170 22895-23066 Sentence denotes Favipiravir also showed an antiviral activity in experimental animals against other RNA viruses, including arenaviruses, alphaviruses, bunyaviruses, and flaviviruses [71].
T171 23067-23193 Sentence denotes Furthermore, preliminary results also indicated that favipiravir potentially possesses a moderate activity against Ebola [72].
T172 23194-23589 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 23590-24063 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 24064-24247 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 24248-24382 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 24383-24579 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 24580-24769 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 24770-24849 Sentence denotes Favipiravir is contraindicated in women with known or suspected pregnancy [75].
T179 24850-24907 Sentence denotes Favipiravir is also associated with QT prolongation [76].
T180 24908-25063 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 25065-25069 Sentence denotes 2.7.
T182 25070-25076 Sentence denotes AT-527
T183 25077-25301 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 25302-25346 Sentence denotes It is a potent inhibitor of viral RdRp [78].
T185 25347-25489 Sentence denotes Following oral administration as hemi-sulfate salt, the drug gets converted to the monophosphate form via multiple metabolic activation steps.
T186 25490-25630 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 25631-25796 Sentence denotes Spontaneous hydrolysis followed by histidine triad nucleotide-binding protein 1 (HINT1)-mediated hydrolysis results in the formation of the monophosphate metabolite.
T188 25797-26103 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 26104-26248 Sentence denotes The safety, pharmacokinetics, and antiviral activity of AT-527 was earlier established in HCV-infected subjects with and without cirrhosis [79].
T190 26249-26455 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 26457-26461 Sentence denotes 2.8.
T192 26462-26471 Sentence denotes EIDD-2801
T193 26472-26544 Sentence denotes It is the isopropyl-ester prodrug of β-D-N4-hydroxycytidine (Figure 5A).
T194 26545-26675 Sentence denotes The prodrug has improved oral bioavailability as it avoids phosphorylation of the N4-hydroxyl group in the gastrointestinal tract.
T195 26676-26838 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 26839-27095 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 27096-27202 Sentence denotes It also demonstrated increased potency against a coronavirus with resistance mutations to remdesivir [82].
T198 27203-27369 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 27370-27552 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 27553-27720 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 27721-27849 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 27850-27917 Sentence denotes The drug produced similar results in human airway epithelial cells.
T203 27918-27992 Sentence denotes The drug showed similar results as a prophylactic and as a treatment [80].
T204 27993-28301 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 28302-28414 Sentence denotes It is now being tested in two phase 2 trials in COVID-19 patients (NCT04405570; n = 44 and NCT04405739; n = 60).
T206 28416-28418 Sentence denotes 3.
T207 28419-28444 Sentence denotes Viral Protease Inhibitors
T208 28446-28450 Sentence denotes 3.1.
T209 28451-28480 Sentence denotes Lopinavir/Ritonavir (Kaletra)
T210 28481-28630 Sentence denotes Lopinavir (Figure 6) is an orally bioavailable, small peptidomimetic antiretroviral agent that acts as an HIV-1 aspartate competitive inhibitor [83].
T211 28631-28766 Sentence denotes The drug inhibits the cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV.
T212 28767-28861 Sentence denotes The inhibition eventually results in the formation of immature, noninfectious viral particles.
T213 28862-28895 Sentence denotes The drug was approved by the U.S.
T214 28896-29003 Sentence denotes FDA in combination with ritonavir (Figure 6), which is another antiretroviral aspartate protease inhibitor.
T215 29004-29206 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 29207-29541 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 29542-29610 Sentence denotes The rationale for using lopinavir is attributed to multiple studies.
T218 29611-29741 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 29742-29886 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 29887-29977 Sentence denotes Earlier, lopinavir exhibited in vitro activity against SARS-CoV-1 and MERS-CoV [88,89,90].
T221 29978-30068 Sentence denotes It also showed beneficial effects in animal studies for the treatment of MERS-CoV [91,92].
T222 30069-30230 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 30231-30390 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 30391-30498 Sentence denotes This subsequently sheds doubts on the prospect of HIV-1 aspartate protease inhibitors in treating COVID-19.
T225 30499-30763 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 30764-31061 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 31062-31211 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 31212-31406 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 31407-31502 Sentence denotes Chest computerized tomography scans were also better in the latter group (29% versus 69%) [96].
T230 31503-31788 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 31789-31917 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 31918-32251 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 32253-32257 Sentence denotes 3.2.
T234 32258-32290 Sentence denotes Darunavir/Cobicistat (Prezcobix)
T235 32291-32410 Sentence denotes Darunavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease [101,102].
T236 32411-32637 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 32638-32680 Sentence denotes Darunavir was approved in 2015 by the U.S.
T238 32681-32767 Sentence denotes FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat.
T239 32768-32955 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 32956-33051 Sentence denotes Darunavir/cobicistat is under clinical investigation for the treatment of SARS-CoV-2 infection.
T241 33052-33207 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 33208-33312 Sentence denotes Mechanistically, this could be because darunavir potentially inhibits 3CLpro and/or PLpro of SARS-CoV-2.
T243 33313-33381 Sentence denotes The two enzymes are important for the viral glycoprotein processing.
T244 33382-33543 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 33544-33700 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 33701-33998 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 33999-34080 Sentence denotes TMC310911 (also known as ASC-09) (Figure 6) is structurally similar to darunavir.
T248 34081-34167 Sentence denotes It is HIV-1 aspartate protease competitive inhibitor with improved antiviral activity.
T249 34168-34362 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 34363-34451 Sentence denotes Similar to darunavir, it was evaluated with the pharmacokinetic booster ritonavir [108].
T251 34452-34551 Sentence denotes Currently, it is being tested in two clinical trials in China in patients infected with SARS-CoV-2.
T252 34552-34661 Sentence denotes It is being tested in combination with ritonavir (NCT04261907; n = 160) or oseltamivir (NCT04261270; n = 60).
T253 34662-34828 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 34830-34834 Sentence denotes 3.3.
T255 34835-34855 Sentence denotes Atazanavir (Reyataz)
T256 34856-34966 Sentence denotes Atazanavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease.
T257 34967-35010 Sentence denotes Atazanavir was approved in 2003 by the U.S.
T258 35011-35157 Sentence denotes FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat (combination is being marketed under the name Evotaz; 2015).
T259 35158-35420 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 35421-35608 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 35609-35679 Sentence denotes In these studies, atazanavir has been identified as inhibitor of Mpro.
T262 35680-35805 Sentence denotes The drug and its combination have been projected to be 10-fold more potent than lopinavir and its combination with ritonavir.
T263 35806-35891 Sentence denotes The drug also inhibited the virus-induced enhancement of IL-6 and TNF-α levels [109].
T264 35892-36048 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 36050-36054 Sentence denotes 3.4.
T266 36055-36075 Sentence denotes Danoprevir/Ritonavir
T267 36076-36188 Sentence denotes Danoprevir (Ganovo) is an orally bioavailable 15-membered macrocyclic peptidomimetic antiviral drug (Figure S4).
T268 36189-36271 Sentence denotes It is an inhibitor of NS3/4A HCV protease, an important processing enzyme complex.
T269 36272-36333 Sentence denotes It inhibits the protease with an IC50 value of 0.29 nM [112].
T270 36334-36397 Sentence denotes It was approved in China in 2018 to treat chronic HCV patients.
T271 36398-36481 Sentence denotes At higher concentrations, it also appears to inhibit the aspartate protease of HIV.
T272 36482-36621 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 36622-36733 Sentence denotes Thus, HCV protease inhibitors, including danoprevir, have been proposed as potential therapeutics for COVID-19.
T274 36734-37030 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 37031-37233 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 37234-37410 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 37411-37609 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 37611-37615 Sentence denotes 3.5.
T279 37616-37637 Sentence denotes Maraviroc (Selzentry)
T280 37638-37923 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 37924-37957 Sentence denotes The drug was approved by the U.S.
T282 37958-38001 Sentence denotes FDA in 2007 as an oral treatment for HIV-1.
T283 38002-38132 Sentence denotes The drug is currently being evaluated in three clinical trials (NCT04441385, NCT04435522, and NCT04475991) for COVID-19 treatment.
T284 38133-38218 Sentence denotes Recently, it was shown that maraviroc may act as a potential inhibitor of Mpro [117].
T285 38219-38432 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 38434-38436 Sentence denotes 4.
T287 38437-38467 Sentence denotes Miscellaneous Antiviral Agents
T288 38469-38473 Sentence denotes 4.1.
T289 38474-38500 Sentence denotes Selinexor (Xpovio, KPT330)
T290 38501-38597 Sentence denotes Selinexor is bis(trifluoromethyl)phenyl-triazole-based antineoplastic small molecule (Figure 7).
T291 38598-38639 Sentence denotes It was first approved in 2019 by the U.S.
T292 38640-38731 Sentence denotes FDA and is being prescribed with dexamethasone for refractory or relapsed multiple myeloma.
T293 38732-38873 Sentence denotes Selinexor is an orally bioavailable, selective inhibitor of chromosome region maintenance 1 (CRM1) protein (also known as exportin 1 (XPO1)).
T294 38874-39000 Sentence denotes CRM1 is the main export factor that shuttles nuclear proteins to the cytoplasm and is typically overexpressed in cancer cells.
T295 39001-39125 Sentence denotes Its selective inhibition can assist in restoring the endogenous tumor-suppressing processes so as to eliminate cancer cells.
T296 39126-39409 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 39410-39485 Sentence denotes This leads to the accumulation of tumor suppressor proteins in the nucleus.
T298 39486-39637 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 39638-39888 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 39889-39993 Sentence denotes Thus, the CRM1 inhibitor selinexor may exert relevant antiviral and anti-inflammatory effects [122,123].
T301 39994-40162 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 40163-40290 Sentence denotes Furthermore, CRM1 inhibition has also been identified in in vitro assays to have a potential activity against SARS-CoV-2 [124].
T303 40291-40411 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 40412-40498 Sentence denotes Thus, CRM1 inhibition is expected to inhibit the viral assembly [125,126,127,128,129].
T305 40499-40680 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 40681-40823 Sentence denotes High levels of CRM1 are found in multiple inflammatory conditions and may magnify inflammatory responses leading to severe organ damage [131].
T307 40824-41034 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 41035-41142 Sentence denotes For example, in a mouse model of sepsis, selinexor increased survival following a lethal dose of endotoxin.
T309 41143-41328 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 41329-41454 Sentence denotes Selinexor also mitigated lipopolysaccharide-induced lung injury that is similar to acute respiratory distress syndrome [132].
T311 41455-41570 Sentence denotes Currently, selinexor is being evaluated in at least two phase 2 randomized trials in the U.S. in COVID-19 patients.
T312 41571-42003 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 42005-42009 Sentence denotes 4.2.
T314 42010-42031 Sentence denotes Nitazoxanide (Alinia)
T315 42032-42136 Sentence denotes It is a nitro-thiazolyl-salicylamide derivative (Figure 7) with a broad-spectrum antimicrobial activity.
T316 42137-42230 Sentence denotes The drug is effective against various helminthic, protozoal, bacterial, and viral infections.
T317 42231-42258 Sentence denotes It was approved by the U.S.
T318 42259-42381 Sentence denotes FDA in 2002 to be used orally for the treatment of diarrhea caused by Cryptosporidium parvum or Giardia lamblia [133,134].
T319 42382-42475 Sentence denotes It is also off-label used for cryptosporidiosis-associated diarrhea in HIV-infected patients.
T320 42476-42600 Sentence denotes The drug has been reported as a broad-spectrum antiviral agent that inhibits the replication of several RNA and DNA viruses.
T321 42601-42743 Sentence denotes Specifically, nitazoxanide has been found to affect influenza A and B viruses as well as neuraminidase inhibitors-resistant influenza viruses.
T322 42744-42980 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 42981-43101 Sentence denotes Some of its activity is also potentially attributed to its active metabolite (tizoxanide), desacetyl-nitazoxanide [136].
T324 43102-43361 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 43362-43409 Sentence denotes The drug is associated with several mechanisms.
T326 43410-43582 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 43583-43801 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 43802-44077 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 44078-44244 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 44245-44389 Sentence denotes The drug was also reported as a non-competitive inhibitor of thiol oxidoreductase ERp57 and thus demonstrated anti-paramyxovirus activity [140].
T331 44390-44544 Sentence denotes Moreover, nitazoxanide was reported to inhibit the production of pro-inflammatory cytokines in peripheral blood mononuclear cells and animal models [136].
T332 44545-44688 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 44689-44838 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 44840-44844 Sentence denotes 4.3.
T335 44845-44852 Sentence denotes NSAIDs:
T336 44853-44896 Sentence denotes Indomethacin (Indocin) and Naproxen (Aleve)
T337 44897-45010 Sentence denotes In one hand, indomethacin is a synthetic, small molecule of N-benzoyl-indole-3-acetic acid derivative (Figure 7).
T338 45011-45044 Sentence denotes It was first approved by the U.S.
T339 45045-45074 Sentence denotes FDA in 1984 for use as NSAID.
T340 45075-45130 Sentence denotes It also possesses analgesic and antipyretic properties.
T341 45131-45174 Sentence denotes It is used for acute mild to moderate pain.
T342 45175-45306 Sentence denotes It is also used for ankylosing spondylitis, bursitis, tendonitis, osteoarthritis, and rheumatoid arthritis, among other conditions.
T343 45307-45460 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 45461-45712 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 45713-46024 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 46025-46124 Sentence denotes Indomethacin blocked the viral RNA synthesis, but not the viral adhesion/entry into the host cells.
T347 46125-46185 Sentence denotes This effect is independent of the cyclooxygenase inhibition.
T348 46186-46322 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 46323-46552 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 46553-46811 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 46812-46947 Sentence denotes Previously, indomethacin also showed antiviral activity against rotavirus infection and vesicular stomatitis virus infection [145,146].
T352 46948-47138 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 47139-47341 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 47342-47463 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 47464-47676 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 47677-47805 Sentence denotes Accordingly, the effect of indomethacin on IL-6 may translate into beneficial effect in treating the cytokine storm of COVID-19.
T357 47806-47938 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 47939-47972 Sentence denotes It was first approved by the U.S.
T359 47973-48235 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 48236-48413 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 48414-48550 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 48551-48657 Sentence denotes In this arena, naproxen antagonized CRM1-mediated nuclear export of proteins of influenza A and B viruses.
T363 48658-48754 Sentence denotes Naproxen also provided therapeutic protection to mice infected with influenza B virus [150,151].
T364 48755-48909 Sentence denotes In hospitalized patients with influenza, it was found that adding clarithromycin and naproxen to oseltamivir shortened the hospitalization time [150,151].
T365 48910-49038 Sentence denotes Naproxen also inhibited the replication of Zika virus by reducing the expression of AXL, the entry cofactor of Zika virus [152].
T366 49039-49220 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 49221-49426 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 49427-49588 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 49590-49594 Sentence denotes 4.4.
T370 49595-49661 Sentence denotes Vidofludimus Calcium (Immunic AG, IMU-838) and Brequinar (DuP-785)
T371 49662-49855 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 49856-49982 Sentence denotes It is a biphenyl-carbamoyl-cyclopentene derivative (Figure 7) that is being developed as oral formulation for therapeutic use.
T373 49983-50215 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 50216-50408 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 50409-50529 Sentence denotes Such inhibition diminishes the pyrimidine pool in these cells, which subsequently exposes the cells to metabolic stress.
T376 50530-50683 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 50684-50902 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 50903-51047 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 51048-51130 Sentence denotes IMU-838 has also effectively promoted antiviral activity against SARS-CoV-2 [157].
T380 51131-51214 Sentence denotes Specifically, IMU-838 inhibited the replication of clinical isolates of SARS-CoV-2.
T381 51215-51400 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 51401-51688 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 51689-51841 Sentence denotes Likewise, brequinar is a synthetic, small molecule, and quinoline-carboxylic acid derivative (Figure 7) that also inhibits dihydroorotate dehydrogenase.
T384 51842-51930 Sentence denotes It eventually blocks the de novo biosynthesis of pyrimidine-based nucleotides [158,159].
T385 51931-51990 Sentence denotes Accordingly, brequinar possesses immunosuppressive effects.
T386 51991-52149 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 52150-52215 Sentence denotes Alternatively, the drug has also antiparasitic effects [160,161].
T388 52216-52373 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 52374-52527 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 52528-52711 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 52713-52717 Sentence denotes 4.5.
T392 52718-52737 Sentence denotes Famotidine (Pepcid)
T393 52738-52853 Sentence denotes Famotidine is a synthetic guandino-thiazole derivative (Figure 7) that acts as a potent and competitive H2-blocker.
T394 52854-52887 Sentence denotes It was first approved by the U.S.
T395 52888-52941 Sentence denotes FDA in 1986 and now is used as over-the-counter drug.
T396 52942-53056 Sentence denotes It can be used orally or parenterally to treat gastroesophageal reflux disease, heartburn, and peptic ulcer [166].
T397 53057-53326 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 53327-53618 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 53619-53961 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 53962-54153 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 54155-54159 Sentence denotes 4.6.
T402 54160-54168 Sentence denotes VERU-111
T403 54169-54342 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 54343-54399 Sentence denotes It has been under clinical development for cancer [170].
T405 54400-54611 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 54612-54785 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 54786-54996 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 54997-55109 Sentence denotes Of note, it is mechanistically similar to colchicine, which has also been considered in COVID-19 patients [172].
T409 55111-55115 Sentence denotes 4.7.
T410 55116-55135 Sentence denotes Leflunomide (Arava)
T411 55136-55222 Sentence denotes It is a synthetic, small molecule and an isoxazole-carboxamide derivative (Figure 8B).
T412 55223-55250 Sentence denotes It was approved by the U.S.
T413 55251-55324 Sentence denotes FDA in 1998 for the oral treatment of rheumatoid arthritis [173,174,175].
T414 55325-55531 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 55532-55634 Sentence denotes Mechanistically, it is a disease-modifying agent with anti-inflammatory and antiproliferative effects.
T416 55635-55813 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 55814-55953 Sentence denotes Leflunomide is a prodrug and the active metabolite (isoxazole ring is open: teriflunomide (Aubagio)) is responsible for its activity [179].
T418 55954-56015 Sentence denotes It inhibits rapidly dividing cells such as activated T cells.
T419 56016-56079 Sentence denotes It has also been found to block the transcription factor NF-κB.
T420 56080-56121 Sentence denotes It also inhibits tyrosine kinase enzymes.
T421 56122-56293 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 56294-56488 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 56490-56494 Sentence denotes 4.8.
T424 56495-56515 Sentence denotes Sirolimus (Rapamune)
T425 56516-56602 Sentence denotes Sirolimus is a natural macrolide (Figure S5) obtained from Streptomyces hygroscopicus.
T426 56603-56636 Sentence denotes It was first approved by the U.S.
T427 56637-56723 Sentence denotes FDA in 1999 and is orally used for lymphangioleiomyomatosis and renal transplantation.
T428 56724-56841 Sentence denotes Mechanistically, the drug is an immunosuppressive agent and an inhibitor of the mammalian target of rapamycin (mTOR).
T429 56842-56982 Sentence denotes Sirolimus forms an immunosuppressive complex with FK-binding protein-12, and subsequently, the complex inhibits the regulatory kinase, mTOR.
T430 56983-57104 Sentence denotes This inhibition suppresses cytokine mediated proliferation of T and B cells as well as the antibody production [180,181].
T431 57105-57261 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 57262-57382 Sentence denotes Furthermore, in vitro studies demonstrated a specific inhibitory activity against MERS-CoV infection by sirolimus [184].
T433 57383-57636 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 57637-57797 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 57798-57958 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 57960-57964 Sentence denotes 4.9.
T437 57965-57986 Sentence denotes Plitidepsin (Aplidin)
T438 57987-58090 Sentence denotes It is a cyclic depsipeptide natural product (Figure S5) that is extracted from Aplidium albicans [186].
T439 58091-58225 Sentence denotes It is used for acute lymphoblastic leukemia and, with dexamethasone, for patients with refractory and relapsed multiple myeloma [187].
T440 58226-58338 Sentence denotes Recently, the molecule was reported to have in vitro nanomolar potency against the human coronavirus 229E [188].
T441 58339-58589 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 58590-58680 Sentence denotes The drug is being tested in phase 1 trial in patients with COVID-19 (NCT04382066; n = 27).
T443 58682-58687 Sentence denotes 4.10.
T444 58688-58712 Sentence denotes Cyclosporine A (Gengraf)
T445 58713-58813 Sentence denotes Cyclosporine A is a cyclic peptide that is naturally obtained from the fungus Beauveria nivea [191].
T446 58814-58902 Sentence denotes It is immunosuppressant and calcineurin inhibitor that inhibits T cell activation [192].
T447 58903-59001 Sentence denotes It binds to the intracellular receptor cyclophilin-1 producing a cyclosporine-cyclophilin complex.
T448 59002-59172 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 59173-59306 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 59307-59350 Sentence denotes Cyclosporine was first approved by the U.S.
T451 59351-59619 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 59620-59807 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 59808-59889 Sentence denotes Cyclosporin A significantly inhibited gene expression and reduced progeny titers.
T454 59890-59974 Sentence denotes Cyclosporin A treatment completely blocked SARS-CoV RNA and protein synthesis [196].
T455 59975-60146 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 60147-60221 Sentence denotes In fact, cyclosporine A has demonstrated broad-spectrum antiviral effects.
T457 60222-60278 Sentence denotes It inhibited the replication of HBV, HCV, and HIV [197].
T458 60279-60524 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 60525-60602 Sentence denotes By targeting cyclophilins, the drug can also prevent acute lung injury [199].
T460 60603-60884 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 60885-60944 Sentence denotes It has also been used in psoriatic COVID-19 patients [200].
T462 60946-60951 Sentence denotes 4.11.
T463 60952-60975 Sentence denotes Deferoxamine (Desferal)
T464 60976-61056 Sentence denotes Deferoxamine (Figure S5) is a natural chelating agent from Streptomyces pilosus.
T465 61057-61090 Sentence denotes It was first approved by the U.S.
T466 61091-61157 Sentence denotes FDA in 1968 and has been parenterally used to treat iron toxicity.
T467 61158-61313 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 61314-61395 Sentence denotes There are reports about unusually high serum ferritin in COVID-19 patients [203].
T469 61396-61546 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 61547-61675 Sentence denotes The increase in serum ferritin indicates dysregulated iron homeostasis pertaining to oxidative stress and inflammatory response.
T471 61676-61866 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 61867-61988 Sentence denotes Accordingly, the use of iron chelators, particularly deferoxamine, in managing/treating COVID-19 has been proposed [208].
T473 61989-62203 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 62204-62310 Sentence denotes In addition to its effect on iron level, deferoxamine also appears to have immunomodulatory effects [209].
T475 62311-62428 Sentence denotes Along these lines, deferoxamine mitigated the symptoms of Enterovirus-infected mice and decreased the mortality rate.
T476 62429-62518 Sentence denotes It also upregulated the B cell levels and improved the neutralizing antibody titer [209].
T477 62519-62666 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 62667-62715 Sentence denotes Deferoxamine may also have antifibrotic effects.
T479 62716-62893 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 62895-62900 Sentence denotes 4.12.
T481 62901-62920 Sentence denotes Atovaquone (Mepron)
T482 62921-63037 Sentence denotes Atovaquone is an orally active, synthetic hydroxy-naphthoquinone derivative (Figure S6) with antiparasitic activity.
T483 63038-63065 Sentence denotes It was approved by the U.S.
T484 63066-63125 Sentence denotes FDA in 1992 against Pneumocystis jirovecii pneumonia [215].
T485 63126-63229 Sentence denotes It has also been used to prevent and/or treat toxoplasmosis, malaria, and babesiosis [216,217,218,219].
T486 63230-63420 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 63421-63650 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 63651-63757 Sentence denotes One potential mechanism of action for atovaquone pertaining to SARS-CoV-2 is the inhibition of Mpro [221].
T489 63758-63827 Sentence denotes Another computational study suggested that it may inhibit RdRp [169].
T490 63828-63908 Sentence denotes Importantly, these computational studies are yet to be experimentally confirmed.
T491 63910-63915 Sentence denotes 4.13.
T492 63916-63926 Sentence denotes Levamisole
T493 63927-64040 Sentence denotes It is a tetrahydro-imidazothiazole derivative (Figure S6) that has been used for its immunomodulatory properties.
T494 64041-64084 Sentence denotes It was first introduced by Janssen in 1969.
T495 64085-64193 Sentence denotes Ever since, it was used as a disease-modifying drug for the treatment of rheumatoid arthritis [222,223,224].
T496 64194-64264 Sentence denotes It was also used with 5-fluorouracil for colon cancer treatment [225].
T497 64265-64455 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 64456-64582 Sentence denotes It is also used by pediatric nephrologists as a steroid-sparing agent in childhood steroid-dependent nephrotic syndrome [227].
T499 64583-64861 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 64862-64921 Sentence denotes Yet, no experimental validation has been reported thus far.
T501 64922-65093 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 65094-65170 Sentence denotes The rationale for this use has been because of its immunomodulatory effects.
T503 65171-65297 Sentence denotes Levamisole acts as an immune-modulator and immune-enhancer by increasing T-cell lymphocyte function and macrophage chemotaxis.
T504 65298-65438 Sentence denotes It has also been shown to up-regulate toll-like receptors, stimulate neutrophil chemotaxis, and enhance dendritic cell maturation [229,230].
T505 65439-65549 Sentence denotes Furthermore, levamisole attenuated alveolar macrophage dysfunction in respiratory virus-infected calves [231].
T506 65551-65556 Sentence denotes 4.14.
T507 65557-65565 Sentence denotes BLD-2660
T508 65566-65714 Sentence denotes It an orally bioavailable, small molecule, reversible covalent inhibitor of calpains, non-lysosomal cysteine proteases, with anti-fibrotic activity.
T509 65715-65886 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 65887-65952 Sentence denotes It exhibited high selectivity against related cysteine proteases.
T511 65953-66056 Sentence denotes Earlier, several calpain inhibitors were found to reduce the viral replication of SARS-CoV-1 [232,233].
T512 66057-66228 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 66229-66348 Sentence denotes Undisclosed inhibitors by the developing company were found to reduce SARS-CoV-2 replication in Vero cell-based assays.
T514 66349-66529 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 66530-66788 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 66790-66795 Sentence denotes 4.15.
T517 66796-66824 Sentence denotes N-Acetylcysteine (Acetadote)
T518 66825-66922 Sentence denotes It is a small molecule in which the amino group of cysteine amino acid is acetylated (Figure S6).
T519 66923-66964 Sentence denotes N-acetylcysteine was approved by the U.S.
T520 66965-67070 Sentence denotes FDA in 1963 for the oral use as mucolytic agent and parenteral use to treat acetaminophen overdose [235].
T521 67071-67167 Sentence denotes Currently, there are about six ongoing clinical trials to evaluate its use in COVID-19 patients.
T522 67168-67284 Sentence denotes The rationale for these studies is attributed to its potential antiviral, antioxidant, and immunomodulatory effects.
T523 67285-67425 Sentence denotes In this arena, several experiments have shown that acetylcysteine may eventually inhibit the viral replication of influenza A [236,237,238].
T524 67426-67529 Sentence denotes Acetylcysteine has also been evaluated for use in the treatment of HIV in two randomized studies [239].
T525 67530-67738 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 67739-67940 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 67941-68082 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 68083-68223 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 68224-68382 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 68384-68389 Sentence denotes 4.16.
T531 68390-68400 Sentence denotes Artesunate
T532 68401-68473 Sentence denotes It is a polycyclic natural product with endoperoxide moiety (Figure S6).
T533 68474-68515 Sentence denotes It is parenterally used to treat malaria.
T534 68516-68650 Sentence denotes Initially, there was not enough information about its efficacy against SARS-CoV, except the results of herbal extract screening [246].
T535 68651-68838 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 68839-68984 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 68985-69158 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 69160-69165 Sentence denotes 4.17.
T539 69166-69201 Sentence denotes Povidone-Iodine Solution (Betadine)
T540 69202-69291 Sentence denotes Povidone-iodine is a chemical complex of polyvinylpyrrolidone polymer and iodine (PVP-I).
T541 69292-69468 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 69469-69646 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 69647-69972 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 69974-69979 Sentence denotes 4.18.
T545 69980-70003 Sentence denotes Chlorhexidine (Peridex)
T546 70004-70126 Sentence denotes Chlorhexidine is a broad-spectrum, guanidino-containing antimicrobial agent (Figure S6) that is widely used as antiseptic.
T547 70127-70214 Sentence denotes It was first approved in the U.S. in 1986 and is used for gingivitis and periodontitis.
T548 70215-70341 Sentence denotes It is also used for the oropharyngeal sanitization to reduce the risk of ventilator-associated or hospital-acquired pneumonia.
T549 70342-70410 Sentence denotes It is used as a skin disinfectant for preoperative skin preparation.
T550 70411-70562 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 70563-70666 Sentence denotes Mechanistically, it has both micro-biostatic and micro-biocidal effects depending on its concentration.
T552 70667-70909 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 70910-71067 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 71068-71312 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 71313-71491 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 71493-71498 Sentence denotes 4.19.
T557 71499-71526 Sentence denotes Methylene Blue (ProvayBlue)
T558 71527-71625 Sentence denotes Methylene blue is disubstituted phenothiazine derivative (Figure S6) that was approved by the U.S.
T559 71626-71680 Sentence denotes FDA for the parenteral treatment of methemoglobinemia.
T560 71681-71740 Sentence denotes It acts by forming leukomethylene blue complex within RBCs.
T561 71741-71838 Sentence denotes The product is a reducing agent that converts the ferric ion back to the ferrous ion state [256].
T562 71839-71903 Sentence denotes Methylene blue has antiviral activity [257,258,259,260,261,262].
T563 71904-72085 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 72086-72238 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 72239-72480 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 72481-72607 Sentence denotes A mice model study also demonstrated the ability of methylene blue plus fluorescent light to inactivate West Nile Virus [262].
T567 72608-72656 Sentence denotes It is also effective against septic shock [263].
T568 72657-72816 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 72817-72953 Sentence denotes It also improves systemic vascular resistance and mean arterial pressure while decreases vasopressor requirements in septic shock [265].
T570 72954-73060 Sentence denotes It also demonstrates anti-inflammatory effects because it can inhibit NLRP3 inflammasome activation [266].
T571 73061-73243 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 73245-73250 Sentence denotes 4.20.
T573 73251-73271 Sentence denotes Inhaled Nitric Oxide
T574 73272-73372 Sentence denotes Nitric oxide is an endogenous signaling molecule that is involved in a host of biological processes.
T575 73373-73501 Sentence denotes The molecule is produced internally by the action of nitric oxide synthase enzyme that catalyzes its production from L-arginine.
T576 73502-73754 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 73755-73909 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 73910-74057 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 74058-74117 Sentence denotes Nitric oxide inhibited the viral protein and RNA synthesis.
T580 74118-74260 Sentence denotes Importantly, the study demonstrated that nitric oxide produced by inducible nitric oxide synthase inhibited the replication of SARS-CoV [270].
T581 74261-74372 Sentence denotes Another study revealed that nitric oxide causes a reduction in the palmitoylation of the viral spike S protein.
T582 74373-74462 Sentence denotes This subsequently impedes the fusion between the viral spike S protein and the host ACE2.
T583 74463-74593 Sentence denotes Moreover, nitric oxide also leads to a substantial decrease in viral RNA production in the early steps of viral replication [271].
T584 74594-74693 Sentence denotes These outcomes were attributed to its potential effect on the cysteine proteases of SARS-CoV [272].
T585 74694-74869 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 74870-75018 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 75019-75079 Sentence denotes The vasodilation is mediated by activating guanylyl cyclase.
T588 75080-75245 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 75246-75334 Sentence denotes Nitric oxide administration also shortened the time needed of ventilation support [274].
T590 75335-75526 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 75527-75654 Sentence denotes Currently, there are about 17 clinical trials being performed to evaluate the use of inhaled nitric oxide in COVID-19 patients.
T592 75655-75950 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 75952-75957 Sentence denotes 4.21.
T594 75958-75972 Sentence denotes Poly-Alcohols:
T595 75973-75998 Sentence denotes Resveratrol and Quercetin
T596 75999-76085 Sentence denotes On the one hand, resveratrol is a natural polyphenolic stilbene derivative (Figure 9).
T597 76086-76235 Sentence denotes Resveratrol exhibits several biological activities, including antioxidant, antitumor, anti-inflammatory, oxygen scavenging, and antiviral activities.
T598 76236-76316 Sentence denotes Resveratrol inhibits TNF-induced activation of NF-κB in a dose-dependent manner.
T599 76317-76386 Sentence denotes Furthermore, it inhibits cyclooxygenase and hydro-peroxidase enzymes.
T600 76387-76511 Sentence denotes Not only that but it also inhibits vascular cell adhesion molecule expression and vascular smooth muscle cell proliferation.
T601 76512-76643 Sentence denotes It also stimulates endothelial nitric oxide synthase activity and inhibits platelet aggregation and LDL peroxidation [276,277,278].
T602 76644-76730 Sentence denotes All these effects are expected to help fight COVID-19 infection and its complications.
T603 76731-76856 Sentence denotes Importantly, resveratrol significantly inhibited MERS-CoV replication in vitro mainly by inhibiting the RNA production [279].
T604 76857-76959 Sentence denotes Resveratrol also inhibited the replication of duck enteritis virus [280] and pseudorabies virus [281].
T605 76960-77145 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 77146-77228 Sentence denotes On the other hand, quercetin is a natural penta-hydroxylated flavonoid (Figure 9).
T607 77229-77353 Sentence denotes Similar to resveratrol, quercetin possesses antioxidant, oxygen scavenging, anti-inflammatory, and cardioprotective effects.
T608 77354-77472 Sentence denotes Quercetin also inhibits platelet aggregation and lipid peroxidation and affects the function of several kinases [282].
T609 77473-77573 Sentence denotes Importantly, quercetin also exhibits a wide spectrum antiviral activity against DNA and RNA viruses.
T610 77574-77653 Sentence denotes For example, quercetin inhibited several respiratory viruses in cultured cells.
T611 77654-77774 Sentence denotes It also inhibited the cytopathic effects of rhinoviruses, echoviruses, coxsackieviruses, and polioviruses [283,284,285].
T612 77775-77928 Sentence denotes Quercetin also significantly reduced plaque formation by polio virus, herpes simplex virus 1, respiratory syncytial virus, and parainfluenza virus [286].
T613 77929-78022 Sentence denotes Furthermore, quercetin inhibited the replication of cytomegalovirus and dengue virus 2 [287].
T614 78023-78190 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 78191-78274 Sentence denotes Other flavonoids have recently been reported as potential inhibitors of Mpro [289].
T616 78275-78409 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 78410-78492 Sentence denotes It is also being tested with zinc, bromelain, and vitamin C (NCT04468139; n = 60).
T618 78494-78499 Sentence denotes 4.22.
T619 78500-78515 Sentence denotes Macromolecules:
T620 78516-78559 Sentence denotes Thymalfasin, Lactoferrin, TY027, and XAV-19
T621 78560-78712 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 78713-78840 Sentence denotes It possesses immunoregulatory properties owing primarily to its ability to activate various immune cells, particularly T cells.
T623 78841-78970 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 78971-79133 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 79134-79214 Sentence denotes Currently, it is being tested in few clinical trials in the context of COVID-19.
T626 79215-79335 Sentence denotes An important study is the trial to prevent COVID-19 infection in elderly renal dialysis patients (NCT04428008; n = 240).
T627 79336-79425 Sentence denotes Lactoferrin is another macromolecule that is being considered in the context of COVID-19.
T628 79426-79566 Sentence denotes It is an iron-binding, multifunctional globular glycoprotein that is widely present in secretory biological fluids, particularly milk [294].
T629 79567-79676 Sentence denotes Lactoferrin exhibits a broad-spectrum antimicrobial activity against bacterial, viral, and fungal infections.
T630 79677-79830 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 79831-80088 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 80089-80164 Sentence denotes Importantly, lactoferrin also appears to exhibit activity against SARS-CoV.
T633 80165-80249 Sentence denotes It was shown that lactoferrin prevented SARS-CoV from entering human cultured cells.
T634 80250-80472 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 80473-80641 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 80642-80868 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 80869-81140 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 81141-81281 Sentence denotes Lastly, other strategies are being clinically evaluated to treat COVID-19 patients as they may produce direct or indirect antiviral effects.
T639 81282-81586 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 81587-81851 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 81852-81939 Sentence denotes Most frequently tested anti-inflammatory/immunomodulatory agents are listed in Table 2.
T642 81940-82068 Sentence denotes Antithrombotic agents that are most frequently being tested in clinical trials for COVID-19 patients are also listed in Table 3.
T643 82070-82072 Sentence denotes 5.
T644 82073-82084 Sentence denotes Conclusions
T645 82085-82145 Sentence denotes The life cycle of SARS-CoV-2 can be divided into two phases.
T646 82146-82255 Sentence denotes On the one hand, events prior to the viral RNA replication represent the early stage of the virus life cycle.
T647 82256-82482 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 82483-82613 Sentence denotes On the other hand, events that involve RNA replication and subsequent processes represent the later stage of the virus life cycle.
T649 82614-82762 Sentence denotes Specifically, it entails the RNA replication process, viral protein synthesis and processing, and viral particle assembly, and mature virus release.
T650 82763-82872 Sentence denotes Notably, events in the two phases are mediated by several interactions among various viral and host proteins.
T651 82873-83006 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 83007-83109 Sentence denotes Furin, TMPRSS2, and cathepsin L enzymes are also important for the early stage of the viral infection.
T653 83110-83263 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 83264-83504 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 83505-83627 Sentence denotes Furthermore, the resulting viral proteins require further processing which takes place by the action of by Mpro and PLpro.
T656 83628-83803 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 83804-83921 Sentence denotes We previously reviewed potential anti-COVID-19 therapeutics that target the early stage in the viral life cycle [12].
T658 83922-84036 Sentence denotes In this review, we summarized potential therapeutics that interfere with the post-entry events of the viral cycle.
T659 84037-84204 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 84205-84304 Sentence denotes In this arena, we described potential therapeutics that are currently listed in clinicaltrials.gov.
T661 84305-84891 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 84892-85072 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 85073-85180 Sentence denotes The described therapeutics also include macromolecules such as thymalfasin, lactoferrin, TY027, and XAV-19.
T664 85181-85316 Sentence denotes Many of the above drugs are currently approved therapeutics for other indications; thus, they present a unique repurposing opportunity.
T665 85317-85428 Sentence denotes Yet, others are new molecular entities such as AR-527, EIDD-2801, ACS-09, vidofludimus, VERU-111, and BLD-2660.
T666 85429-85601 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 85602-85711 Sentence denotes Furthermore, many of the presented therapeutics promote pharmacological effects beyond the antiviral effects.
T668 85712-85830 Sentence denotes Of note are the anti-inflammatory/immune-modulatory effects of selinexor, NSAIDs, VERU-111, leflunomide, and BLD-2660.
T669 85831-85950 Sentence denotes These effects are of enormous significance due to the confirmed excessive inflammation in the severe cases of COVID-19.
T670 85951-86172 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 86173-86463 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 86464-86649 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 86650-86781 Sentence denotes Based on initial results, remdesivir, favipiravir, EIDD-2801, and selinexor appear to carry the most promising therapeutic effects.
T674 86782-86815 Sentence denotes In fact, on May 1, 2020, the U.S.
T675 86816-87002 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 87003-87165 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].
T677 87167-87190 Sentence denotes Supplementary Materials
T678 87191-87285 Sentence denotes The following are available online at https://www.mdpi.com/1999-4915/12/10/1092/s1, Figure S1:
T679 87286-87404 Sentence denotes The chemical structure of tenofovir disoproxil and schematic representation of its metabolic bioactivation, Figure S2:
T680 87405-87524 Sentence denotes The chemical structure of tenofovir alafenamide and schematic representation of its metabolic bioactivation, Figure S3:
T681 87525-87629 Sentence denotes The chemical structure of AT-527 and schematic representation of its metabolic bioactivation, Figure S4:
T682 87630-87692 Sentence denotes The chemical structure of danoprevir and maraviroc, Figure S5:
T683 87693-87803 Sentence denotes The chemical structures of three natural products that are currently being tested against COVID-19, Figure S6:
T684 87804-87913 Sentence denotes The chemical structures of various agents with potential antiviral activity attributed to various mechanisms.
T685 87914-87950 Sentence denotes Click here for additional data file.
T686 87952-87972 Sentence denotes Author Contributions
T687 87973-88222 Sentence denotes Conceptualization, R.A.A.-H.; writing—original draft preparation, R.A.A.-H. and S.K.; writing—review and editing, R.A.A.-H. and S.K.; visualization, R.A.A.-H.; supervision, R.A.A.-H.; project administration, R.A.A.-H.; funding acquisition, R.A.A.-H.
T688 88223-88299 Sentence denotes All authors have read and agreed to the published version of the manuscript.
T689 88301-88308 Sentence denotes Funding
T690 88309-88446 Sentence denotes R.A.A.-H. is supported by grants from National Institute of General Medical Sciences under the award numbers SC3GM131986 and P20GM103424.
T691 88447-88564 Sentence denotes The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH.
T692 88566-88587 Sentence denotes Conflicts of Interest
T693 88588-88632 Sentence denotes The authors declare no conflict of interest.
T694 88633-88817 Sentence denotes The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
T695 88818-88831 Sentence denotes Abbreviations
T696 88832-88868 Sentence denotes 3CLpro 3-Chymotrypsin-like protease
T697 88869-88906 Sentence denotes ACE2 Angiotensin converting enzyme 2
T698 88907-88949 Sentence denotes ADALP1 Adenosine deaminase like protein 1
T699 88950-88974 Sentence denotes CES1 Carboxylesterase 1
T700 88975-89023 Sentence denotes COVID-19 Coronavirus infectious disease of 2019
T701 89024-89061 Sentence denotes CRM1 Chromosome region maintenance 1
T702 89062-89121 Sentence denotes ERGIC Endoplasmic reticulum–Golgi intermediate compartment
T703 89122-89149 Sentence denotes GTP Guanosine triphosphate
T704 89150-89174 Sentence denotes GUK1 Guanylate kinase 1
T705 89175-89226 Sentence denotes HINT1 Histidine triad nucleotide-binding protein 1
T706 89227-89249 Sentence denotes HBV Hepatitis B virus
T707 89250-89272 Sentence denotes HCV Hepatitis C virus
T708 89273-89306 Sentence denotes HIV Human immunodeficiency virus
T709 89307-89322 Sentence denotes INF Interferon
T710 89323-89338 Sentence denotes IL Interleukin
T711 89339-89393 Sentence denotes MERS-CoV Middle East respiratory syndrome coronavirus
T712 89394-89413 Sentence denotes Mpro Main protease
T713 89414-89449 Sentence denotes NDPK Nucleoside diphosphate kinase
T714 89450-89494 Sentence denotes NSAIDs Nonsteroidal anti-inflammatory drugs
T715 89495-89521 Sentence denotes NSP Nonstructural protein
T716 89522-89564 Sentence denotes NF-AT Nuclear factor of activated T-cells
T717 89565-89600 Sentence denotes mTOR Mammalian target of rapamycin
T718 89601-89628 Sentence denotes PLpro Papain-like protease
T719 89629-89663 Sentence denotes RdRp RNA-dependent RNA polymerase
T720 89664-89719 Sentence denotes SARS-CoV Severe acute respiratory syndrome coronavirus
T721 89720-89779 Sentence denotes SARS-CoV-2 Severe acute respiratory syndrome coronavirus-2
T722 89780-89820 Sentence denotes TRMPSS2 Transmembrane protease serine 2
T723 89822-89921 Sentence denotes Figure 1 Representation of the viral particle of SARS-CoV-2 demonstrating the structural proteins:
T724 89922-89975 Sentence denotes S (blue), E (brownish orange), M (red), and N (pink).
T725 89976-90045 Sentence denotes It also details the post-entry stages of the life cycle of the virus.
T726 90046-90264 Sentence denotes Following the release of the viral RNA genome to the host cell environment, the nonstructural proteins (NSPs) domain is expressed as two polypeptides and eventually produce PLpro, Mpro (also known as 3CLpro), and RdRp.
T727 90265-90370 Sentence denotes Initial processing of the two polypeptides is by host proteases and then is propagated by PLpro and Mpro.
T728 90371-90464 Sentence denotes The viral RdRp is also responsible for the replication and amplification of the viral genome.
T729 90465-90688 Sentence denotes The viral RNA and the N structural protein are biosynthesized in the host cell cytoplasm, whereas viral structural proteins S, M, and E are biosynthesized in the endoplasmic reticulum and transported to the Golgi apparatus.
T730 90689-90761 Sentence denotes The viral RNA–N complex and S, M, and E proteins are assembled in ERGIC.
T731 90762-90814 Sentence denotes The mature virus is produced by the budding process.
T732 90815-90856 Sentence denotes The virus is then released by exocytosis.
T733 90857-90862 Sentence denotes Note:
T734 90863-91067 Sentence denotes The virus enters via membrane fusion in the endo/lyso-somes which requires proteolytic activation by cathepsins (a) or via fusion at the cell membrane which requires proteolytic activation by TMPRSS2 (b).
T735 91068-91224 Sentence denotes Furin may also contribute to the entry of the virus, yet its site of action is not fully established. gRNA means genomic RNA and sgRNA means subgenomic RNA.
T736 91225-91328 Sentence denotes Figure 2 Chemical structure of remdesivir and schematic representation of its metabolic bioactivation.
T737 91329-91423 Sentence denotes Remdesivir is adenosine monophosphate derivative; it is also classified as nucleotide prodrug.
T738 91424-91531 Sentence denotes The corresponding triphosphate form is the active form and it is the inhibitor of the viral RNA polymerase.
T739 91532-91768 Sentence denotes Figure 3 Chemical structures of potential RNA polymerase inhibitors, all of which are nucleoside derivatives that undergo tri-phosphorylation activation to form the corresponding nucleoside triphosphate metabolites as the active forms.
T740 91769-91886 Sentence denotes Emtricitabine is being tested in COVID-19 patients in combination with tenofovir disoproxil or tenofovir alafenamide.
T741 91887-92003 Sentence denotes The activation schemes for tenofovir disoproxil or tenofovir alafenamide are provided in the supplementary document.
T742 92004-92077 Sentence denotes Figure 4 Chemical structure of favipiravir and its metabolic activation.
T743 92078-92171 Sentence denotes Critical for its activation is the action of hypoxanthine guanine phosphoribosyl-transferase.
T744 92172-92297 Sentence denotes Figure 5 (A) Chemical structure of EIDD-2801, an isopropyl ester prodrug of ribonucleoside analog of β-D-N4-hydroxycytidine.
T745 92298-92397 Sentence denotes EIDD-2801 is an orally bioavailable nucleoside derivative that is under development for SARS-CoV-2.
T746 92398-92789 Sentence denotes Also depicted is its activation to the corresponding tri-phosphorylated form which exhibits a broad-spectrum antiviral activity against various RNA viruses, including coronaviruses with resistance mutations to remdesivir. (B) The active form exists in two forms: the oxime form which mimics uridine and pairs with adenosine, while the other tautomer mimics cytidine and pairs with guanosine.
T747 92790-92845 Sentence denotes The drug eventually leads to a viral error catastrophe.
T748 92846-93027 Sentence denotes Figure 6 Chemical structures of HIV-1 aspartate protease inhibitors (except cobicistat) that are currently being tested as potential inhibitors of proteases relevant to SARS-CoV-2.
T749 93028-93082 Sentence denotes Ritonavir and cobicistat are pharmacokinetic boosters.
T750 93083-93164 Sentence denotes The most frequent tested combination in COVID-19 patients is lopinavir/ritonavir.
T751 93165-93239 Sentence denotes Figure 7 Chemical structures of miscellaneous potential antiviral agents.
T752 93240-93413 Sentence denotes Of note, the antiviral activity of two NSAIDs (indomethacin and naproxen) and the antiviral activity of dihydroorotate dehydrogenase inhibitors (vidofludimus and brequinar).
T753 93414-93490 Sentence denotes Many of these drugs also exhibit anti-inflammatory/immunomodulatory effects.
T754 93491-93561 Sentence denotes Figure 8 (A) The chemical structure of investigational drug VERU-111.
T755 93562-93756 Sentence denotes The drug exhibits broad antiviral activity because it disrupts the intracellular transport of viruses, including SARS CoV-2, along microtubules, which is critical for viruses to cause infection.
T756 93757-93891 Sentence denotes It also promotes strong anti-inflammatory effects. (B) The chemical structures of leflunomide and its active metabolite teriflunomide.
T757 93892-94060 Sentence denotes Their potential therapeutic values in COVID-19 patients are attributed to antiviral effects by dihydroorotate dehydrogenase inhibition and to anti-inflammatory effects.
T758 94061-94275 Sentence denotes Figure 9 Chemical structures of two naturally occurring polyphenols, i.e., resveratrol and quercetin with a host of beneficial biological effects including antiviral, anti-inflammatory, and antioxidant activities.
T759 94276-94438 Sentence denotes Table 1 Potential anti-COVID-19 therapeutics that are being tested in clinical trials based on targeting the post-entry events of the life cycle of SARS-CoV-2 a.
T760 94439-94466 Sentence denotes Viral Polymerase Inhibitors
T761 94467-94516 Sentence denotes Remdesivir Emtricitabine & tenofovir alafenamide
T762 94517-94541 Sentence denotes Galidesivir Favipiravir
T763 94542-94559 Sentence denotes Ribavirin AT-527
T764 94560-94580 Sentence denotes Clevudine EIDD-2801
T765 94581-94617 Sentence denotes Emtricitabine & tenofovir disoproxil
T766 94618-94643 Sentence denotes Viral protease inhibitors
T767 94644-94675 Sentence denotes Lopinavir/ritonavir Atazanavir
T768 94676-94718 Sentence denotes Darunavir/cobicistat Danoprevir/ritonavir
T769 94719-94736 Sentence denotes ASC-09 Maraviroc
T770 94737-94767 Sentence denotes Miscellaneous antiviral agents
T771 94768-94789 Sentence denotes Selinexor Levamisole
T772 94790-94812 Sentence denotes Nitazoxanide BLD-2660
T773 94813-94867 Sentence denotes NSAIDs (Indomethacin and naproxen) b N-Acetylcysteine
T774 94868-94892 Sentence denotes Vidofludimus Artesunate
T775 94893-94928 Sentence denotes Brequinar Povidone-iodine solution
T776 94929-94954 Sentence denotes Famotidine Chlorhexidine
T777 94955-94979 Sentence denotes VERU-111 Methylene blue
T778 94980-95013 Sentence denotes Leflunomide Inhaled nitric oxide
T779 95014-95064 Sentence denotes Sirolimus Poly-alcohols (Resveratrol & quercetin)
T780 95065-95089 Sentence denotes Plitidepsin Thymalfasin
T781 95090-95115 Sentence denotes Cyclosporine Lactoferrin
T782 95116-95135 Sentence denotes Deferoxamine TY027
T783 95136-95154 Sentence denotes Atovaquone XAV-19
T784 95155-95224 Sentence denotes a Some of the listed therapeutics have multiple antiviral mechanisms.
T785 95225-95331 Sentence denotes Some also have anti-inflammatory effects. b NSAIDs is an acronym for nonsteroidal anti-inflammatory drugs.
T786 95332-95442 Sentence denotes Table 2 Most frequently evaluated anti-inflammatory/immunomodulatory drugs in clinical trials for COVID-19 a.
T787 95443-95508 Sentence denotes Therapy Type Mechanism No. of Interventional Clinical Trials b
T788 95509-95588 Sentence denotes Tocilizumab(Actemra) Humanized monoclonal antibody IL-6 receptor blocker ~41
T789 95589-95652 Sentence denotes Ruxolitinib(Jakafi) Small molecule JAK 1 and 2 inhibitor ~15
T790 95653-95761 Sentence denotes Colchicine(Colcrys) Small molecule Inhibition of NLRP3 inflammasome and of microtubule polymerization ~15
T791 95762-95858 Sentence denotes Anakinra(Kineret) Recombinant non-glycosylated human polypeptide IL-1 receptor antagonist ~13
T792 95859-96033 Sentence denotes Methylprednisolone (DEPOMedrol) Small molecule Intracellular receptor-mediated gene expression & suppression of migration of polymorphonuclear leukocytes, among others ~13
T793 96034-96099 Sentence denotes Baricitinib(Olumiant) Small molecule JAK 1 and 2 inhibitor ~12
T794 96100-96173 Sentence denotes Sarilumab(Kevzara) Human monoclonal antibody IL-6 receptor blocker ~10
T795 96174-96416 Sentence denotes Dexamethasone(Decadron, Active Injection D) Small molecule Stimulation of glucocorticoid receptors, suppression of neutrophil migration, suppression of inflammatory mediators production, and reversal of increased capillary permeability ~10
T796 96417-96480 Sentence denotes Sirolimus(Rapamune) Small molecule mTOR pathway inhibitor ~4
T797 96481-96549 Sentence denotes Mavrilimumab Human monoclonal antibody GM-CSF receptor blocker ~4
T798 96550-96614 Sentence denotes Siltuximab(Sylvant) Chimeric monoclonal antibody Anti-IL-6 ~2
T799 96615-96677 Sentence denotes Canakinumab(Ilaris) Human monoclonal antibody Anti-IL-1β ~2
T800 96678-96734 Sentence denotes a From clinicaltrials.gov, b No. is as of July 25, 2020.
T801 96735-96753 Sentence denotes Abbreviations: IL:
T802 96754-96771 Sentence denotes Interleukin; JAK:
T803 96772-96916 Sentence denotes Janus kinase; NLRP3: NOD-like receptor protein 3; mTOR: mammalian target of rapamycin; GM-CSF: granulocyte macrophage colony-stimulating factor.
T804 96917-97002 Sentence denotes Table 3 Most frequently evaluated antithrombotics in clinical trials for COVID-19 a.
T805 97003-97068 Sentence denotes Therapy Type Mechanism No. of Interventional Clinical Trials b
T806 97069-97269 Sentence denotes Unfractionated heparin or Low molecular weight heparins (Enoxaparin, Dalteparin, Tinzaparin, and others) Sulfated glycosaminoglycans Activation of antithrombin to inhibit thrombin and factor Xa ~23
T807 97270-97347 Sentence denotes Aspirin (Acetylsalicylic acid) Small molecule Cyclo-oxygenase inhibitor ~8
T808 97348-97416 Sentence denotes Rivaroxaban(Xarelto) Small molecule Direct factor Xa inhibitor ~5
T809 97417-97527 Sentence denotes Dipyridamole(Aggrenox) Small molecule Nucleoside transport inhibitor and a phosphodiesterase 3 inhibitor ~3
T810 97528-97620 Sentence denotes Clopidogrel(Plavix) Small molecule Irreversible adenosine diphosphate receptor blocker ~3
T811 97621-97676 Sentence denotes a From clinicaltrials.gov, b No. is as of 25 July 2020.