LitCovid-sentences  

PMC:7600245 / 38434-82068 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T286 0-2 Sentence denotes 4.
T287 3-33 Sentence denotes Miscellaneous Antiviral Agents
T288 35-39 Sentence denotes 4.1.
T289 40-66 Sentence denotes Selinexor (Xpovio, KPT330)
T290 67-163 Sentence denotes Selinexor is bis(trifluoromethyl)phenyl-triazole-based antineoplastic small molecule (Figure 7).
T291 164-205 Sentence denotes It was first approved in 2019 by the U.S.
T292 206-297 Sentence denotes FDA and is being prescribed with dexamethasone for refractory or relapsed multiple myeloma.
T293 298-439 Sentence denotes Selinexor is an orally bioavailable, selective inhibitor of chromosome region maintenance 1 (CRM1) protein (also known as exportin 1 (XPO1)).
T294 440-566 Sentence denotes CRM1 is the main export factor that shuttles nuclear proteins to the cytoplasm and is typically overexpressed in cancer cells.
T295 567-691 Sentence denotes Its selective inhibition can assist in restoring the endogenous tumor-suppressing processes so as to eliminate cancer cells.
T296 692-975 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 976-1051 Sentence denotes This leads to the accumulation of tumor suppressor proteins in the nucleus.
T298 1052-1203 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 1204-1454 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 1455-1559 Sentence denotes Thus, the CRM1 inhibitor selinexor may exert relevant antiviral and anti-inflammatory effects [122,123].
T301 1560-1728 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 1729-1856 Sentence denotes Furthermore, CRM1 inhibition has also been identified in in vitro assays to have a potential activity against SARS-CoV-2 [124].
T303 1857-1977 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 1978-2064 Sentence denotes Thus, CRM1 inhibition is expected to inhibit the viral assembly [125,126,127,128,129].
T305 2065-2246 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 2247-2389 Sentence denotes High levels of CRM1 are found in multiple inflammatory conditions and may magnify inflammatory responses leading to severe organ damage [131].
T307 2390-2600 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 2601-2708 Sentence denotes For example, in a mouse model of sepsis, selinexor increased survival following a lethal dose of endotoxin.
T309 2709-2894 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 2895-3020 Sentence denotes Selinexor also mitigated lipopolysaccharide-induced lung injury that is similar to acute respiratory distress syndrome [132].
T311 3021-3136 Sentence denotes Currently, selinexor is being evaluated in at least two phase 2 randomized trials in the U.S. in COVID-19 patients.
T312 3137-3569 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 3571-3575 Sentence denotes 4.2.
T314 3576-3597 Sentence denotes Nitazoxanide (Alinia)
T315 3598-3702 Sentence denotes It is a nitro-thiazolyl-salicylamide derivative (Figure 7) with a broad-spectrum antimicrobial activity.
T316 3703-3796 Sentence denotes The drug is effective against various helminthic, protozoal, bacterial, and viral infections.
T317 3797-3824 Sentence denotes It was approved by the U.S.
T318 3825-3947 Sentence denotes FDA in 2002 to be used orally for the treatment of diarrhea caused by Cryptosporidium parvum or Giardia lamblia [133,134].
T319 3948-4041 Sentence denotes It is also off-label used for cryptosporidiosis-associated diarrhea in HIV-infected patients.
T320 4042-4166 Sentence denotes The drug has been reported as a broad-spectrum antiviral agent that inhibits the replication of several RNA and DNA viruses.
T321 4167-4309 Sentence denotes Specifically, nitazoxanide has been found to affect influenza A and B viruses as well as neuraminidase inhibitors-resistant influenza viruses.
T322 4310-4546 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 4547-4667 Sentence denotes Some of its activity is also potentially attributed to its active metabolite (tizoxanide), desacetyl-nitazoxanide [136].
T324 4668-4927 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 4928-4975 Sentence denotes The drug is associated with several mechanisms.
T326 4976-5148 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 5149-5367 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 5368-5643 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 5644-5810 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 5811-5955 Sentence denotes The drug was also reported as a non-competitive inhibitor of thiol oxidoreductase ERp57 and thus demonstrated anti-paramyxovirus activity [140].
T331 5956-6110 Sentence denotes Moreover, nitazoxanide was reported to inhibit the production of pro-inflammatory cytokines in peripheral blood mononuclear cells and animal models [136].
T332 6111-6254 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 6255-6404 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 6406-6410 Sentence denotes 4.3.
T335 6411-6418 Sentence denotes NSAIDs:
T336 6419-6462 Sentence denotes Indomethacin (Indocin) and Naproxen (Aleve)
T337 6463-6576 Sentence denotes In one hand, indomethacin is a synthetic, small molecule of N-benzoyl-indole-3-acetic acid derivative (Figure 7).
T338 6577-6610 Sentence denotes It was first approved by the U.S.
T339 6611-6640 Sentence denotes FDA in 1984 for use as NSAID.
T340 6641-6696 Sentence denotes It also possesses analgesic and antipyretic properties.
T341 6697-6740 Sentence denotes It is used for acute mild to moderate pain.
T342 6741-6872 Sentence denotes It is also used for ankylosing spondylitis, bursitis, tendonitis, osteoarthritis, and rheumatoid arthritis, among other conditions.
T343 6873-7026 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 7027-7278 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 7279-7590 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 7591-7690 Sentence denotes Indomethacin blocked the viral RNA synthesis, but not the viral adhesion/entry into the host cells.
T347 7691-7751 Sentence denotes This effect is independent of the cyclooxygenase inhibition.
T348 7752-7888 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 7889-8118 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 8119-8377 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 8378-8513 Sentence denotes Previously, indomethacin also showed antiviral activity against rotavirus infection and vesicular stomatitis virus infection [145,146].
T352 8514-8704 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 8705-8907 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 8908-9029 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 9030-9242 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 9243-9371 Sentence denotes Accordingly, the effect of indomethacin on IL-6 may translate into beneficial effect in treating the cytokine storm of COVID-19.
T357 9372-9504 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 9505-9538 Sentence denotes It was first approved by the U.S.
T359 9539-9801 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 9802-9979 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 9980-10116 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 10117-10223 Sentence denotes In this arena, naproxen antagonized CRM1-mediated nuclear export of proteins of influenza A and B viruses.
T363 10224-10320 Sentence denotes Naproxen also provided therapeutic protection to mice infected with influenza B virus [150,151].
T364 10321-10475 Sentence denotes In hospitalized patients with influenza, it was found that adding clarithromycin and naproxen to oseltamivir shortened the hospitalization time [150,151].
T365 10476-10604 Sentence denotes Naproxen also inhibited the replication of Zika virus by reducing the expression of AXL, the entry cofactor of Zika virus [152].
T366 10605-10786 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 10787-10992 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 10993-11154 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 11156-11160 Sentence denotes 4.4.
T370 11161-11227 Sentence denotes Vidofludimus Calcium (Immunic AG, IMU-838) and Brequinar (DuP-785)
T371 11228-11421 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 11422-11548 Sentence denotes It is a biphenyl-carbamoyl-cyclopentene derivative (Figure 7) that is being developed as oral formulation for therapeutic use.
T373 11549-11781 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 11782-11974 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 11975-12095 Sentence denotes Such inhibition diminishes the pyrimidine pool in these cells, which subsequently exposes the cells to metabolic stress.
T376 12096-12249 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 12250-12468 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 12469-12613 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 12614-12696 Sentence denotes IMU-838 has also effectively promoted antiviral activity against SARS-CoV-2 [157].
T380 12697-12780 Sentence denotes Specifically, IMU-838 inhibited the replication of clinical isolates of SARS-CoV-2.
T381 12781-12966 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 12967-13254 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 13255-13407 Sentence denotes Likewise, brequinar is a synthetic, small molecule, and quinoline-carboxylic acid derivative (Figure 7) that also inhibits dihydroorotate dehydrogenase.
T384 13408-13496 Sentence denotes It eventually blocks the de novo biosynthesis of pyrimidine-based nucleotides [158,159].
T385 13497-13556 Sentence denotes Accordingly, brequinar possesses immunosuppressive effects.
T386 13557-13715 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 13716-13781 Sentence denotes Alternatively, the drug has also antiparasitic effects [160,161].
T388 13782-13939 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 13940-14093 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 14094-14277 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 14279-14283 Sentence denotes 4.5.
T392 14284-14303 Sentence denotes Famotidine (Pepcid)
T393 14304-14419 Sentence denotes Famotidine is a synthetic guandino-thiazole derivative (Figure 7) that acts as a potent and competitive H2-blocker.
T394 14420-14453 Sentence denotes It was first approved by the U.S.
T395 14454-14507 Sentence denotes FDA in 1986 and now is used as over-the-counter drug.
T396 14508-14622 Sentence denotes It can be used orally or parenterally to treat gastroesophageal reflux disease, heartburn, and peptic ulcer [166].
T397 14623-14892 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 14893-15184 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 15185-15527 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 15528-15719 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 15721-15725 Sentence denotes 4.6.
T402 15726-15734 Sentence denotes VERU-111
T403 15735-15908 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 15909-15965 Sentence denotes It has been under clinical development for cancer [170].
T405 15966-16177 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 16178-16351 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 16352-16562 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 16563-16675 Sentence denotes Of note, it is mechanistically similar to colchicine, which has also been considered in COVID-19 patients [172].
T409 16677-16681 Sentence denotes 4.7.
T410 16682-16701 Sentence denotes Leflunomide (Arava)
T411 16702-16788 Sentence denotes It is a synthetic, small molecule and an isoxazole-carboxamide derivative (Figure 8B).
T412 16789-16816 Sentence denotes It was approved by the U.S.
T413 16817-16890 Sentence denotes FDA in 1998 for the oral treatment of rheumatoid arthritis [173,174,175].
T414 16891-17097 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 17098-17200 Sentence denotes Mechanistically, it is a disease-modifying agent with anti-inflammatory and antiproliferative effects.
T416 17201-17379 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 17380-17519 Sentence denotes Leflunomide is a prodrug and the active metabolite (isoxazole ring is open: teriflunomide (Aubagio)) is responsible for its activity [179].
T418 17520-17581 Sentence denotes It inhibits rapidly dividing cells such as activated T cells.
T419 17582-17645 Sentence denotes It has also been found to block the transcription factor NF-κB.
T420 17646-17687 Sentence denotes It also inhibits tyrosine kinase enzymes.
T421 17688-17859 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 17860-18054 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 18056-18060 Sentence denotes 4.8.
T424 18061-18081 Sentence denotes Sirolimus (Rapamune)
T425 18082-18168 Sentence denotes Sirolimus is a natural macrolide (Figure S5) obtained from Streptomyces hygroscopicus.
T426 18169-18202 Sentence denotes It was first approved by the U.S.
T427 18203-18289 Sentence denotes FDA in 1999 and is orally used for lymphangioleiomyomatosis and renal transplantation.
T428 18290-18407 Sentence denotes Mechanistically, the drug is an immunosuppressive agent and an inhibitor of the mammalian target of rapamycin (mTOR).
T429 18408-18548 Sentence denotes Sirolimus forms an immunosuppressive complex with FK-binding protein-12, and subsequently, the complex inhibits the regulatory kinase, mTOR.
T430 18549-18670 Sentence denotes This inhibition suppresses cytokine mediated proliferation of T and B cells as well as the antibody production [180,181].
T431 18671-18827 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 18828-18948 Sentence denotes Furthermore, in vitro studies demonstrated a specific inhibitory activity against MERS-CoV infection by sirolimus [184].
T433 18949-19202 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 19203-19363 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 19364-19524 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 19526-19530 Sentence denotes 4.9.
T437 19531-19552 Sentence denotes Plitidepsin (Aplidin)
T438 19553-19656 Sentence denotes It is a cyclic depsipeptide natural product (Figure S5) that is extracted from Aplidium albicans [186].
T439 19657-19791 Sentence denotes It is used for acute lymphoblastic leukemia and, with dexamethasone, for patients with refractory and relapsed multiple myeloma [187].
T440 19792-19904 Sentence denotes Recently, the molecule was reported to have in vitro nanomolar potency against the human coronavirus 229E [188].
T441 19905-20155 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 20156-20246 Sentence denotes The drug is being tested in phase 1 trial in patients with COVID-19 (NCT04382066; n = 27).
T443 20248-20253 Sentence denotes 4.10.
T444 20254-20278 Sentence denotes Cyclosporine A (Gengraf)
T445 20279-20379 Sentence denotes Cyclosporine A is a cyclic peptide that is naturally obtained from the fungus Beauveria nivea [191].
T446 20380-20468 Sentence denotes It is immunosuppressant and calcineurin inhibitor that inhibits T cell activation [192].
T447 20469-20567 Sentence denotes It binds to the intracellular receptor cyclophilin-1 producing a cyclosporine-cyclophilin complex.
T448 20568-20738 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 20739-20872 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 20873-20916 Sentence denotes Cyclosporine was first approved by the U.S.
T451 20917-21185 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 21186-21373 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 21374-21455 Sentence denotes Cyclosporin A significantly inhibited gene expression and reduced progeny titers.
T454 21456-21540 Sentence denotes Cyclosporin A treatment completely blocked SARS-CoV RNA and protein synthesis [196].
T455 21541-21712 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 21713-21787 Sentence denotes In fact, cyclosporine A has demonstrated broad-spectrum antiviral effects.
T457 21788-21844 Sentence denotes It inhibited the replication of HBV, HCV, and HIV [197].
T458 21845-22090 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 22091-22168 Sentence denotes By targeting cyclophilins, the drug can also prevent acute lung injury [199].
T460 22169-22450 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 22451-22510 Sentence denotes It has also been used in psoriatic COVID-19 patients [200].
T462 22512-22517 Sentence denotes 4.11.
T463 22518-22541 Sentence denotes Deferoxamine (Desferal)
T464 22542-22622 Sentence denotes Deferoxamine (Figure S5) is a natural chelating agent from Streptomyces pilosus.
T465 22623-22656 Sentence denotes It was first approved by the U.S.
T466 22657-22723 Sentence denotes FDA in 1968 and has been parenterally used to treat iron toxicity.
T467 22724-22879 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 22880-22961 Sentence denotes There are reports about unusually high serum ferritin in COVID-19 patients [203].
T469 22962-23112 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 23113-23241 Sentence denotes The increase in serum ferritin indicates dysregulated iron homeostasis pertaining to oxidative stress and inflammatory response.
T471 23242-23432 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 23433-23554 Sentence denotes Accordingly, the use of iron chelators, particularly deferoxamine, in managing/treating COVID-19 has been proposed [208].
T473 23555-23769 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 23770-23876 Sentence denotes In addition to its effect on iron level, deferoxamine also appears to have immunomodulatory effects [209].
T475 23877-23994 Sentence denotes Along these lines, deferoxamine mitigated the symptoms of Enterovirus-infected mice and decreased the mortality rate.
T476 23995-24084 Sentence denotes It also upregulated the B cell levels and improved the neutralizing antibody titer [209].
T477 24085-24232 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 24233-24281 Sentence denotes Deferoxamine may also have antifibrotic effects.
T479 24282-24459 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 24461-24466 Sentence denotes 4.12.
T481 24467-24486 Sentence denotes Atovaquone (Mepron)
T482 24487-24603 Sentence denotes Atovaquone is an orally active, synthetic hydroxy-naphthoquinone derivative (Figure S6) with antiparasitic activity.
T483 24604-24631 Sentence denotes It was approved by the U.S.
T484 24632-24691 Sentence denotes FDA in 1992 against Pneumocystis jirovecii pneumonia [215].
T485 24692-24795 Sentence denotes It has also been used to prevent and/or treat toxoplasmosis, malaria, and babesiosis [216,217,218,219].
T486 24796-24986 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 24987-25216 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 25217-25323 Sentence denotes One potential mechanism of action for atovaquone pertaining to SARS-CoV-2 is the inhibition of Mpro [221].
T489 25324-25393 Sentence denotes Another computational study suggested that it may inhibit RdRp [169].
T490 25394-25474 Sentence denotes Importantly, these computational studies are yet to be experimentally confirmed.
T491 25476-25481 Sentence denotes 4.13.
T492 25482-25492 Sentence denotes Levamisole
T493 25493-25606 Sentence denotes It is a tetrahydro-imidazothiazole derivative (Figure S6) that has been used for its immunomodulatory properties.
T494 25607-25650 Sentence denotes It was first introduced by Janssen in 1969.
T495 25651-25759 Sentence denotes Ever since, it was used as a disease-modifying drug for the treatment of rheumatoid arthritis [222,223,224].
T496 25760-25830 Sentence denotes It was also used with 5-fluorouracil for colon cancer treatment [225].
T497 25831-26021 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 26022-26148 Sentence denotes It is also used by pediatric nephrologists as a steroid-sparing agent in childhood steroid-dependent nephrotic syndrome [227].
T499 26149-26427 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 26428-26487 Sentence denotes Yet, no experimental validation has been reported thus far.
T501 26488-26659 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 26660-26736 Sentence denotes The rationale for this use has been because of its immunomodulatory effects.
T503 26737-26863 Sentence denotes Levamisole acts as an immune-modulator and immune-enhancer by increasing T-cell lymphocyte function and macrophage chemotaxis.
T504 26864-27004 Sentence denotes It has also been shown to up-regulate toll-like receptors, stimulate neutrophil chemotaxis, and enhance dendritic cell maturation [229,230].
T505 27005-27115 Sentence denotes Furthermore, levamisole attenuated alveolar macrophage dysfunction in respiratory virus-infected calves [231].
T506 27117-27122 Sentence denotes 4.14.
T507 27123-27131 Sentence denotes BLD-2660
T508 27132-27280 Sentence denotes It an orally bioavailable, small molecule, reversible covalent inhibitor of calpains, non-lysosomal cysteine proteases, with anti-fibrotic activity.
T509 27281-27452 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 27453-27518 Sentence denotes It exhibited high selectivity against related cysteine proteases.
T511 27519-27622 Sentence denotes Earlier, several calpain inhibitors were found to reduce the viral replication of SARS-CoV-1 [232,233].
T512 27623-27794 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 27795-27914 Sentence denotes Undisclosed inhibitors by the developing company were found to reduce SARS-CoV-2 replication in Vero cell-based assays.
T514 27915-28095 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 28096-28354 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 28356-28361 Sentence denotes 4.15.
T517 28362-28390 Sentence denotes N-Acetylcysteine (Acetadote)
T518 28391-28488 Sentence denotes It is a small molecule in which the amino group of cysteine amino acid is acetylated (Figure S6).
T519 28489-28530 Sentence denotes N-acetylcysteine was approved by the U.S.
T520 28531-28636 Sentence denotes FDA in 1963 for the oral use as mucolytic agent and parenteral use to treat acetaminophen overdose [235].
T521 28637-28733 Sentence denotes Currently, there are about six ongoing clinical trials to evaluate its use in COVID-19 patients.
T522 28734-28850 Sentence denotes The rationale for these studies is attributed to its potential antiviral, antioxidant, and immunomodulatory effects.
T523 28851-28991 Sentence denotes In this arena, several experiments have shown that acetylcysteine may eventually inhibit the viral replication of influenza A [236,237,238].
T524 28992-29095 Sentence denotes Acetylcysteine has also been evaluated for use in the treatment of HIV in two randomized studies [239].
T525 29096-29304 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 29305-29506 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 29507-29648 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 29649-29789 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 29790-29948 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 29950-29955 Sentence denotes 4.16.
T531 29956-29966 Sentence denotes Artesunate
T532 29967-30039 Sentence denotes It is a polycyclic natural product with endoperoxide moiety (Figure S6).
T533 30040-30081 Sentence denotes It is parenterally used to treat malaria.
T534 30082-30216 Sentence denotes Initially, there was not enough information about its efficacy against SARS-CoV, except the results of herbal extract screening [246].
T535 30217-30404 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 30405-30550 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 30551-30724 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 30726-30731 Sentence denotes 4.17.
T539 30732-30767 Sentence denotes Povidone-Iodine Solution (Betadine)
T540 30768-30857 Sentence denotes Povidone-iodine is a chemical complex of polyvinylpyrrolidone polymer and iodine (PVP-I).
T541 30858-31034 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 31035-31212 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 31213-31538 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 31540-31545 Sentence denotes 4.18.
T545 31546-31569 Sentence denotes Chlorhexidine (Peridex)
T546 31570-31692 Sentence denotes Chlorhexidine is a broad-spectrum, guanidino-containing antimicrobial agent (Figure S6) that is widely used as antiseptic.
T547 31693-31780 Sentence denotes It was first approved in the U.S. in 1986 and is used for gingivitis and periodontitis.
T548 31781-31907 Sentence denotes It is also used for the oropharyngeal sanitization to reduce the risk of ventilator-associated or hospital-acquired pneumonia.
T549 31908-31976 Sentence denotes It is used as a skin disinfectant for preoperative skin preparation.
T550 31977-32128 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 32129-32232 Sentence denotes Mechanistically, it has both micro-biostatic and micro-biocidal effects depending on its concentration.
T552 32233-32475 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 32476-32633 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 32634-32878 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 32879-33057 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 33059-33064 Sentence denotes 4.19.
T557 33065-33092 Sentence denotes Methylene Blue (ProvayBlue)
T558 33093-33191 Sentence denotes Methylene blue is disubstituted phenothiazine derivative (Figure S6) that was approved by the U.S.
T559 33192-33246 Sentence denotes FDA for the parenteral treatment of methemoglobinemia.
T560 33247-33306 Sentence denotes It acts by forming leukomethylene blue complex within RBCs.
T561 33307-33404 Sentence denotes The product is a reducing agent that converts the ferric ion back to the ferrous ion state [256].
T562 33405-33469 Sentence denotes Methylene blue has antiviral activity [257,258,259,260,261,262].
T563 33470-33651 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 33652-33804 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 33805-34046 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 34047-34173 Sentence denotes A mice model study also demonstrated the ability of methylene blue plus fluorescent light to inactivate West Nile Virus [262].
T567 34174-34222 Sentence denotes It is also effective against septic shock [263].
T568 34223-34382 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 34383-34519 Sentence denotes It also improves systemic vascular resistance and mean arterial pressure while decreases vasopressor requirements in septic shock [265].
T570 34520-34626 Sentence denotes It also demonstrates anti-inflammatory effects because it can inhibit NLRP3 inflammasome activation [266].
T571 34627-34809 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 34811-34816 Sentence denotes 4.20.
T573 34817-34837 Sentence denotes Inhaled Nitric Oxide
T574 34838-34938 Sentence denotes Nitric oxide is an endogenous signaling molecule that is involved in a host of biological processes.
T575 34939-35067 Sentence denotes The molecule is produced internally by the action of nitric oxide synthase enzyme that catalyzes its production from L-arginine.
T576 35068-35320 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 35321-35475 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 35476-35623 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 35624-35683 Sentence denotes Nitric oxide inhibited the viral protein and RNA synthesis.
T580 35684-35826 Sentence denotes Importantly, the study demonstrated that nitric oxide produced by inducible nitric oxide synthase inhibited the replication of SARS-CoV [270].
T581 35827-35938 Sentence denotes Another study revealed that nitric oxide causes a reduction in the palmitoylation of the viral spike S protein.
T582 35939-36028 Sentence denotes This subsequently impedes the fusion between the viral spike S protein and the host ACE2.
T583 36029-36159 Sentence denotes Moreover, nitric oxide also leads to a substantial decrease in viral RNA production in the early steps of viral replication [271].
T584 36160-36259 Sentence denotes These outcomes were attributed to its potential effect on the cysteine proteases of SARS-CoV [272].
T585 36260-36435 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 36436-36584 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 36585-36645 Sentence denotes The vasodilation is mediated by activating guanylyl cyclase.
T588 36646-36811 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 36812-36900 Sentence denotes Nitric oxide administration also shortened the time needed of ventilation support [274].
T590 36901-37092 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 37093-37220 Sentence denotes Currently, there are about 17 clinical trials being performed to evaluate the use of inhaled nitric oxide in COVID-19 patients.
T592 37221-37516 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 37518-37523 Sentence denotes 4.21.
T594 37524-37538 Sentence denotes Poly-Alcohols:
T595 37539-37564 Sentence denotes Resveratrol and Quercetin
T596 37565-37651 Sentence denotes On the one hand, resveratrol is a natural polyphenolic stilbene derivative (Figure 9).
T597 37652-37801 Sentence denotes Resveratrol exhibits several biological activities, including antioxidant, antitumor, anti-inflammatory, oxygen scavenging, and antiviral activities.
T598 37802-37882 Sentence denotes Resveratrol inhibits TNF-induced activation of NF-κB in a dose-dependent manner.
T599 37883-37952 Sentence denotes Furthermore, it inhibits cyclooxygenase and hydro-peroxidase enzymes.
T600 37953-38077 Sentence denotes Not only that but it also inhibits vascular cell adhesion molecule expression and vascular smooth muscle cell proliferation.
T601 38078-38209 Sentence denotes It also stimulates endothelial nitric oxide synthase activity and inhibits platelet aggregation and LDL peroxidation [276,277,278].
T602 38210-38296 Sentence denotes All these effects are expected to help fight COVID-19 infection and its complications.
T603 38297-38422 Sentence denotes Importantly, resveratrol significantly inhibited MERS-CoV replication in vitro mainly by inhibiting the RNA production [279].
T604 38423-38525 Sentence denotes Resveratrol also inhibited the replication of duck enteritis virus [280] and pseudorabies virus [281].
T605 38526-38711 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 38712-38794 Sentence denotes On the other hand, quercetin is a natural penta-hydroxylated flavonoid (Figure 9).
T607 38795-38919 Sentence denotes Similar to resveratrol, quercetin possesses antioxidant, oxygen scavenging, anti-inflammatory, and cardioprotective effects.
T608 38920-39038 Sentence denotes Quercetin also inhibits platelet aggregation and lipid peroxidation and affects the function of several kinases [282].
T609 39039-39139 Sentence denotes Importantly, quercetin also exhibits a wide spectrum antiviral activity against DNA and RNA viruses.
T610 39140-39219 Sentence denotes For example, quercetin inhibited several respiratory viruses in cultured cells.
T611 39220-39340 Sentence denotes It also inhibited the cytopathic effects of rhinoviruses, echoviruses, coxsackieviruses, and polioviruses [283,284,285].
T612 39341-39494 Sentence denotes Quercetin also significantly reduced plaque formation by polio virus, herpes simplex virus 1, respiratory syncytial virus, and parainfluenza virus [286].
T613 39495-39588 Sentence denotes Furthermore, quercetin inhibited the replication of cytomegalovirus and dengue virus 2 [287].
T614 39589-39756 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 39757-39840 Sentence denotes Other flavonoids have recently been reported as potential inhibitors of Mpro [289].
T616 39841-39975 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 39976-40058 Sentence denotes It is also being tested with zinc, bromelain, and vitamin C (NCT04468139; n = 60).
T618 40060-40065 Sentence denotes 4.22.
T619 40066-40081 Sentence denotes Macromolecules:
T620 40082-40125 Sentence denotes Thymalfasin, Lactoferrin, TY027, and XAV-19
T621 40126-40278 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 40279-40406 Sentence denotes It possesses immunoregulatory properties owing primarily to its ability to activate various immune cells, particularly T cells.
T623 40407-40536 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 40537-40699 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 40700-40780 Sentence denotes Currently, it is being tested in few clinical trials in the context of COVID-19.
T626 40781-40901 Sentence denotes An important study is the trial to prevent COVID-19 infection in elderly renal dialysis patients (NCT04428008; n = 240).
T627 40902-40991 Sentence denotes Lactoferrin is another macromolecule that is being considered in the context of COVID-19.
T628 40992-41132 Sentence denotes It is an iron-binding, multifunctional globular glycoprotein that is widely present in secretory biological fluids, particularly milk [294].
T629 41133-41242 Sentence denotes Lactoferrin exhibits a broad-spectrum antimicrobial activity against bacterial, viral, and fungal infections.
T630 41243-41396 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 41397-41654 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 41655-41730 Sentence denotes Importantly, lactoferrin also appears to exhibit activity against SARS-CoV.
T633 41731-41815 Sentence denotes It was shown that lactoferrin prevented SARS-CoV from entering human cultured cells.
T634 41816-42038 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 42039-42207 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 42208-42434 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 42435-42706 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 42707-42847 Sentence denotes Lastly, other strategies are being clinically evaluated to treat COVID-19 patients as they may produce direct or indirect antiviral effects.
T639 42848-43152 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 43153-43417 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 43418-43505 Sentence denotes Most frequently tested anti-inflammatory/immunomodulatory agents are listed in Table 2.
T642 43506-43634 Sentence denotes Antithrombotic agents that are most frequently being tested in clinical trials for COVID-19 patients are also listed in Table 3.