Repurposable Drug Candidates are Potential Therapeutic Target against Global SARS-CoV-2 Crisis
Abstract
This review provides a pharmacological approach to combat Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) based on two comprehensive denominations which could be specifically intended for viral replication process by either inhibiting essential genomic viral enzymes or preventing viral entry to human cells. These denominations focused on immune therapies either to improve innate antiviral immune responses or to reduce impairment triggered by underactive inflammatory reactions. A variety of drug candidates are available which can inhibit SARS-CoV-2 infection and replication, comprising serine protease inhibitors: Transmembrane Orotease/Serine Subfamily member 2 (TMPRSS2), camostat mesylate, nafamostat mesylate, and angiotensin-converting enzyme inhibitors. This review is also concerned with identifying drugs and ongoing clinical trials with their mechanisms of action against SARS-CoV-2. Chloroquine and hydroxychloroquine, monoclonal antibody, off-label antiviral drugs, nucleotide analog remdesivir and broad-spectrum antiviral drugs also could be used as inhibitors of SARS-CoV-2. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs), dexamethasone, and antiviral phytochemicals that are currently reachable, can prevent SARS-CoV-2 pandemic morbidity and mortality.
Keywords: COVID-19; Antiviral drugs; NSAIDs; ACE2; Clinical trials
Keywords:
COVID-19, Antiviral drugs, NSAIDs, ACE2, Clinical trialsDOI
https://doi.org/10.22270/jddt.v10i5-s.4343References
Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, Pan P, Wang W, Hu D, Liu X, Zhang Q. Coronavirus infections and immune responses. Journal of medical virology, 2020; 92(4):424-32. DOI: 10.1002/jmv.25685
Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature, 2013; 495(7440):251-4. DOI: 10.1038/nature12005
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 2020;181(2):271-280.e8
Kruse RL. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000Research, 2020; 9. https://doi.org/10.1016/j.cell.2020.02.052
Tamanna N, Saha CA, Khan CM, Shah AM, Faruk HM. A review of recent progress and control measures of severe coronavirus disease (COVID-19) outbreak. World Journal of Advanced Research and Reviews, 2020; 7(1):149-61. https://doi.org/10.30574/wjarr.2020.7.1.0236
Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell discovery, 2020; 6(1):1-8. https://doi.org/10.1038/s41421-020-0153-3
Glowacka I, Bertram S, Müller MA, Allen P, Soilleux E, Pfefferle S, Steffen I, Tsegaye TS, He Y, Gnirss K, Niemeyer D. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. Journal of virology, 2011; 85(9):4122-34. DOI: 10.1128/JVI.02232-10
Ramsey ML, Nuttall J, Hart PA. A phase 1/2 trial to evaluate the pharmacokinetics, safety, and efficacy of NI-03 in patients with chronic pancreatitis: study protocol for a randomized controlled trial on the assessment of camostat treatment in chronic pancreatitis (TACTIC). Trials, 2019; 20(1):501. DOI: 10.1186/s13063-019-3606-y
De Savi C, Hughes DL, Kvaerno L. Quest for a COVID-19 Cure by Repurposing Small Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for Supply. Organic Process Research & Development, 2020; 24(6):940–976. https://doi.org/10.1021/acs.oprd.0c00233
Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, Liu YM, Zhao YC, Huang X, Lin L, Xia M. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circulation Research, 2020; 126:1671–1681. https://doi.org/10.1161/CIRCRESAHA.120.317134
Li G, Hu R, Zhang X. Antihypertensive treatment with ACEI/ARB of patients with COVID-19 complicated by hypertension. Hypertens Res, 2020; 43:588–590. https://doi.org/10.1038/s41440-020-0433-1
Cheng H, Wang Y, Wang GQ. Organ‐protective effect of angiotensin‐converting enzyme 2 and its effect on the prognosis of COVID‐19. Journal of medical virology, 2020; 92(7):726-730. DOI: 10.1002/jmv.25785
Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Del Pozo CH, Prosper F, Romero JP. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell, 2020; 181(4):905-913.e7. https://doi.org/10.1016/j.cell.2020.04.004
Hirota M, Shimosegawa T, Kitamura K, Takeda K, Takeyama Y, Mayumi T, Ito T, Takenaka M, Iwasaki E, Sawano H, Ishida E. Continuous regional arterial infusion versus intravenous administration of the protease inhibitor nafamostat mesilate for predicted severe acute pancreatitis: a multicenter, randomized, open-label, phase 2 trial. Journal of gastroenterology, 2020; 55(3):342-52. doi: 10.1007/s00535-019-01644-z
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 2020; 30(3):269-71. https://doi.org/10.1038/s41422-020-0282-0
Bailly C. Cepharanthine: An update of its mode of action, pharmacological properties and medical applications. Phytomedicine, 2019; 62:152956. https://doi.org/10.1016/j.phymed.2019.152956
Fan HH, Wang LQ, Liu WL, An XP, Liu ZD, He XQ, Song LH, Tong YG. Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model. Chinese medical journal, 2020; 133(9):1051–1056. doi: 10.1097/CM9.0000000000000797
Mina F, Rahman M, Das S, Karmakar S, Billah M. Potential Drug Candidates Underway Several Registered Clinical Trials for Battling COVID-19. 2020.
Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases, 2020; 71(15):732–739. https://doi.org/10.1093/cid/ciaa237
Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ, 2020; 192(17):E450-3. DOI: https://doi.org/10.1503/cmaj.200528
Zhou B, Zhang J, Liu Y, Hong W, Jian F, Wang M, Tan J, Cai W, Zhang F, Li L. Safety review of 42 cases of COVID-19 treated with low-dose chloroquine. Infectious Diseases, Preprint: 2020; DOI:10.21203/rs.3.rs-22918/v1
Chorin E, Dai M, Shulman E, Wadhwani L, Cohen RB, Barbhaiya C, Aizer A, Holmes D, Bernstein S, Soinelli M, Park DS. The QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine and azithromycin. Nat Med, 2020; 26:808–809. https://doi.org/10.1038/s41591-020-0888-2
Borba M, de Almeida Val F, Sampaio VS, Alexandre MA, Melo GC, Brito M, Mourao M, Sousa JD, Guerra MV, Hajjar L, Pinto RC. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). MedRxiv, 2020; doi: 10.1001/jamanetworkopen.2020.8857
Jung JY, Kim MY, Suh CH, Kim HA. Off-label use of tocilizumab to treat non-juvenile idiopathic arthritis in pediatric rheumatic patients: a literature review. Pediatric Rheumatology, 2018; 16(1):79. DOI: 10.1186/s12969-018-0296-z
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. Jama, 2020; 323(18):1824-36. doi:10.1001/jama.2020.6019
Bimonte S, Crispo A, Amore A, Celentano E, Cuomo A, Cascella M. Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research. In Vivo, 2020; 34(3 suppl):1597-602. doi: 10.21873/invivo.11949
Pandey A, Nikam AN, Shreya AB, Mutalik SP, Gopalan D, Kulkarni S, Padya BS, Fernandes G, Mutalik S, Prassl R. Potential therapeutic targets for combating SARS-CoV-2: Drug repurposing, clinical trials and recent advancements. Life Sciences, 2020; 1:117883. https://doi.org/10.1016/j.lfs.2020.117883
Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 2020; 368(6489):409-12. DOI: 10.1126/science.abb3405
Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrobial agents and chemotherapy, 1998; 42(12):3218-24. doi: 10.1128/AAC.42.12.3218.
Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax, 2004; 59(3):252-6. http://dx.doi.org/10.1136/thorax.2003.012658
Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, Mo X, Wang J, Wang Y, Peng P, Chen X. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). MedRxiv, 2020; doi: 10.1016/j.medj.2020.04.001
Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. New England Journal of Medicine, 2020; 382(19):1787-1799. doi: 10.1056/NEJMoa2001282.
Wu J, Li W, Shi X, Chen Z, Jiang B, Liu J, Wang D, Liu C, Meng Y, Cui L, Yu J. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID‐19). Journal of internal medicine, 2020; 288(1):128-138. doi:10.1111/joim.13063
Akhtar MJ. COVID19 inhibitors: a prospective therapeutics. Bioorg. Chem, 2020; 101:104027. doi: 10.1016/j.bioorg.2020.104027.
Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature, 2016; 531(7594):381-5. https://doi.org/10.1038/nature17180
Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio, 2018; 9:e00221-18. DOI: 10.1128/mBio.00221-18
Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson K, Wilkerson S, Tural A, Diaz G. First case of 2019 novel coronavirus in the United States. N Engl J Med, 2020; 382:929-936. DOI: 10.1056/NEJMoa2001191
Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery, 2020; 19:149-150. doi: 10.1038/d41573-020-00016-0
Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis, 2020; 71(15):769-777. doi:10.1093/cid/ciaa272
Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proceedings of the Japan Academy, Series B, 2017; 93(7):449-63. DOI:10.2183/pjab.93.027
Du YX, Chen XP. Favipiravir: pharmacokinetics and concerns about clinical trials for 2019‐nCoV infection. Clin. Pharmacol. Ther. 2020; 108:190. https://doi.org/10.1002/cpt.1878
Bai CQ, Mu JS, Kargbo D, Song YB, Niu WK, Nie WM, Kanu A, Liu WW, Wang YP, Dafae F, Yan T. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)—Sierra Leone, 2014. Clinical Infectious Diseases, 2016; 63(10):1288-94. https://doi.org/10.1093/cid/ciw571
Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, Liao X, Gu Y, Cai Q, Yang Y, Shen C. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering, 2020; In press, https://doi.org/10.1016/j.eng.2020.03.007
Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International journal of antimicrobial agents, 2020; 20:105949. doi: 10.1016/j.ijantimicag.2020.105949
Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M, Luo Y, Zhang J, Yin P. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. MedRxiv, 2020 Jan 1.
Shim A, Song JH, Kwon BE, Lee JJ, Ahn JH, Kim YJ, Rhee KJ, Chang SY, Cha Y, Lee YS, Kweon MN. Therapeutic and prophylactic activity of itraconazole against human rhinovirus infection in a murine model. Sci Rep, 2016; 6:23110. https://doi.org/10.1038/srep23110
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The lancet, 2020; 395(10223):497-506. DOI:10.1016/S0140-6736(20)30183-5
Chu CK, Gadthula S, Chen X, Choo H, Olgen S, Barnard DL, Sidwell RW. Antiviral activity of nucleoside analogues against SARS-coronavirus (SARS-CoV). Antiviral Chemistry and Chemotherapy, 2006; 17(5):285-9. DOI: 10.1177/095632020601700506
Puerta-Arias JD, Pino-Tamayo PA, Arango JC, Salazar-Peláez LM, González A. Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis. Medical mycology, 2018; 56(5):579-90. DOI: 10.1093/mmy/myx087
Jesus FP, Ferreiro L, Loreto ÉS, Pilotto MB, Ludwig A, Bizzi K, Tondolo JS, Zanette RA, Alves SH, Santurio JM. In vitro synergism observed with azithromycin, clarithromycin, minocycline, or tigecycline in association with antifungal agents against Pythium insidiosum. Antimicrobial agents and chemotherapy, 2014; 58(9):5621-5. DOI: 10.1128/AAC.02349-14
Rut W, Groborz K, Zhang L, Sun X, Zmudzinski M, Hilgenfeld R, Drag M. Substrate specificity profiling of SARS-CoV-2 Mpro protease provides basis for anti-COVID-19 drug design. Biorxiv, 2020, preprint, doi: https://doi.org/10.1101/2020.03.07.981928 .
Jeon S, Ko M, Lee J, Choi I, Byun SY, Park S, Shum D, Kim S. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrob Agents Chemother, 2020; 64:e00819-20. https://doi.org/10 .1128/AAC.00819-20.
Liu YC, Huang V, Chao TC, Hsiao CD, Lin A, Chang MF, Chow LP. Screening of drugs by FRET analysis identifies inhibitors of SARS-CoV 3CL protease. Biochem Biophys Res Commun, 2005; 333(1):194-9. doi: 10.1016/j.bbrc.2005.05.095
Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, Duan Y. Structure of M pro from SARS-CoV-2 and discovery of its inhibitors. Nature, 2020; 582:289–293. https://doi.org/10.1038/s41586-020-2223-y
Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F, Li C. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science, 2020; 368(6497):1331-1335. DOI: 10.1126/science.abb4489
Fan S, Xiao D, Wang Y, Liu L, Zhou X, Zhong W. Research progress on repositioning drugs and specific therapeutic drugs for SARS-CoV-2. Future Med Chem, 2020; 10.4155/fmc-2020-0158.
DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, Kotzin S, Laine C, Marusic A, Overbeke AJ, Schroeder TV. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med, 2004; 351:1250-1251. DOI:10.1056/NEJMe048225
Lythgoe MP, Middleton P. Ongoing clinical trials for the management of the COVID-19 pandemic. Tren Pharmacol Sci, 2020; 41(6):363-382. https://doi.org/10.1016/j.tips.2020.03.006
Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax, 2004; 59(3):252-6. doi: 10.1136/thorax.2003.012658
Tu YF, Chien CS, Yarmishyn AA, Lin YY, Luo YH, Lin YT, Lai WY, Yang DM, Chou SJ, Yang YP, Wang ML. A review of SARS-CoV-2 and the ongoing clinical trials. Int J Mol Sci, 2020; 21(7):2657. doi: 10.3390/ijms21072657
Voiriot G, Philippot Q, Elabbadi A, Elbim C, Chalumeau M, Fartoukh M. Risks related to the use of non-steroidal anti-inflammatory drugs in community-acquired pneumonia in adult and pediatric patients. Journal of clinical medicine, 2019; 8(6):786. doi: 10.3390/jcm8060786
Little P. Non-steroidal anti-inflammatory drugs and covid-19. BMJ, 2020; 368 doi: https://doi.org/10.1136/bmj.m1185
Chaiamnuay S, Allison JJ, Curtis JR. Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs. American journal of health-system pharmacy, 2006; 63(19):1837-51. https://doi.org/10.2146/ajhp050519
Fang L, Karakiulakis G, Roth M. Antihypertensive drugs and risk of COVID-19?–Authors' reply. Lancet Respir Med, 2020; 8(5):e32. https://doi.org/10.1016/S2213-2600(20)30116-8
Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ, 2020; 368 doi: https://doi.org/10.1136/bmj.m1086
Pyrillou K, Chairakaki AD, Tamvakopoulos C, Andreakos E. Dexamethasone induces ω3-derived immunoresolvents driving resolution of allergic airway inflammation. J Allergy Clin Immunol, 2018; 142(2):691-695.e4. doi: 10.1016/j.jaci.2018.04.004.
Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature, 2014; 510(7503):92-101. DOI: 10.1038/nature13479
Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B. Dexamethasone in Hospitalized Patients with Covid-19-Preliminary Report. N Eng J Med, 2020; DOI: 10.1056/NEJMoa2021436
Lim H, Min DS, Park H, Kim HP. Flavonoids interfere with NLRP3 inflammasome activation. Toxicology and applied pharmacology, 2018; 355:93-102. https://doi.org/10.1016/j.taap.2018.06.022
Yamagata K, Hashiguchi K, Yamamoto H, Tagami M. Dietary apigenin reduces induction of LOX-1 and NLRP3 expression, leukocyte adhesion, and acetylated low-density lipoprotein uptake in human endothelial cells exposed to trimethylamine-N-oxide. J Cardiovasc Pharmacol, 2019; 74(6):558-65. doi: 10.1097/FJC.0000000000000747.
Ho TY, Wu SL, Chen JC, Li CC, Hsiang CY. Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral research, 2007; 74(2):92-101. https://doi.org/10.1016/j.antiviral.2006.04.014
Lin SC, Ho CT, Chuo WH, Li S, Wang TT, Lin CC. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect Dis, 2017; 17:144. https://doi.org/10.1186/s12879-017-2253-8
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