A Review on Drug Repurposing: A Strategy to Treat Human Coronavirus Disease (COVID-19)

Main Article Content

Neetu Bhattacharya
Shashank Kumar Maurya
Sabyasachi Senapati
Amit Bhattacharya

Abstract

Novel coronavirus pandemic has created a massive public health emergency causing around 1.85 million deaths world-wide till 5th January, 2021. New SARS (Severe Acute Respiratory Syndrome) coronavirus strain known as SARS-CoV-2 is the causative agent which infected more than 84 million people across the globe. Current epicentre of the pandemic has shifted to Europe and United States and Indian subcontinent from its place of origin-Wuhan City, Hubei province in China. Due to limited availability of vaccines against SARS-CoV-2 or its related β-coronavirus (SARS-CoV or MERS-CoV), mass immunization is currently not possible. Thus, use of curative therapies could be the only choice of intervention. Therefore, rapid treatment of millions of COVID-19 patients in limited time can only be achieved by repurposing pre-approved and existing drugs. Network-based high-throughput computational approach has also predicted several repurposable drugs. Cheaper, less toxic and well tolerated drugs such as antimalarial drugs: Chloroquine (CQ) & Hydroxychloroquine (HCQ); antiviral drugs: Remdesivir, Lopinavir and Ritonavir are among many others that have been proposed for the COVID-19 treatment. Presently limited controlled clinical trials are underway to assess the therapeutic outcome of these repurposed drugs along with novel candidate vaccines and medicines. Beside these, convalescent plasma therapy has also emerged as potential therapeutic approach being tested in several countries. This review focuses on few of the promising repurposed drugs and their outcomes that are presently under evaluation for their safety and efficacy against the coronavirus disease 2019 (COVID-19).

Keywords:
COVID-19, drug repurposing, remdesivir, lopinavir, ritonavir, hydroxychloroquine

Article Details

How to Cite
Bhattacharya, N., Maurya, S. K., Senapati, S., & Bhattacharya, A. (2020). A Review on Drug Repurposing: A Strategy to Treat Human Coronavirus Disease (COVID-19). International Journal of TROPICAL DISEASE & Health, 41(21), 42-54. https://doi.org/10.9734/ijtdh/2020/v41i2130407
Section
Review Article

References

Zheng J, SARS-CoV-2: An emerging coronavirus that causes a global threat. Int J Biol Sci. 2020;16:1678–1685. DOI:10.7150/ijbs.45053

World Health Organization. Coronavirus disease (COVID-19) Dashboard, as on 5th January, 2021. Available: covid19.who.int

Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials. Gov. results database--update and key issues. N Engl J Med. 2011;364:852–860. DOI:10.1056/NEJMsa1012065

Chong CR, Sullivan DJ, New uses for old drugs. Nature. 2007;448:645-646. DOI:10.1038/448645a

Raju TN. The Nobel chronicles. 1988: James Whyte Black, (b 1924), Gertrude Elion (1918-99), and George H Hitchings (1905-98). Lancet. 2000;355:1022. DOI: 10.1016/s0140-6736(05)74775-9

Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect. 2009;22: 119-125. DOI:10.1358/dnp.2009.22.2.1303818

Ashburn TT, Thor KB, Drug repositioning: Identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004; 3:673–683. DOI: 10.1038/nrd1468

DRAFT landscape of COVID-19 candidate vaccines; 2020. Available:https://www.who.int/blueprint/priority-diseases/key-action/Novel-Coronavirus_Landscape_nCoV-4april2020.pdf?ua=1

Rosa SGV, Santos WC, Clinical trials on drug repositioning for COVID-19 treatment. Rev. Panam. Salud. Publica. 2020;44:40. DOI: 10.26633/RPSP.2020.40

Cascella M, Rajnik M, Cuomo A et al. Features, evaluation and treatment coronavirus (COVID-19). In: StatPearls. treasure island (FL): Stat Pearls Publishing; 2020. Available:https://www.ncbi.nlm.nih.gov/books/NBK554776/

Zhang L, Lin D, Sun X et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;eabb3405. DOI: 10.1126/science.abb3405

Xu Y, Cong L, Chen C et al. Crystal structures of two coronavirus ADP-ribose-1''-monophosphatases and their complexes with ADP-Ribose: A systematic structural analysis of the viral ADRP domain. J Virol. 2009;83:1083–1092. DOI:10.1128/JVI.01862-08

Kim Y, Jedrzejczak R, Maltseva NI et al. Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2. bioRxiv; 2020. DOI:10.1101 /2020.03.02.968388

Littler DR, Gully BS, Colson RN et al. Crystal structure of the SARS-CoV-2 non-structural protein 9, Nsp9. bioRxiv. 2020. DOI:10.1101/2020.03. 28.013920

Zhou Y, Hou Y, Shen J et al. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020;6:14. DOI:10.1038/s41421-020-0153-3

Gordon DE, Jang GM, Bouhaddu M et al. A SARS-CoV-2 Human protein-protein interaction map reveals drug targets and potential drug-repositioning. Biorxiv. 2020. DOI:10.1101/2020.03.22.002386

Cava C, Bertoli G, Castiglioni I. In Silico Discovery of Candidate Drugs against Covid-19. Viruses. 2020;12:E404. DOI:10.3390/v12040404

Li ZX, Yu J, Zhang et al. Network bioinformatics analysis provides insight into drug repositioning for COVID-2019. Preprints. 2020. DOI:10.20944/preprints202003.0286.v1

Slater AF, Chloroquine: Mechanism of drug action and resistance in Plasmodium falciparum. Pharmacology & Therapeutics. 1993;57:203-235. DOI: 10.1016/0163-7258(93)90056-j

McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am. J. Med. 1983;75:11–18. DOI:10.1016/0002-9343(83)91265-2

White NJ. Chapter 43: Malaria. Manson’s tropical infectious diseases (Twenty-Third Edition), 2014;532-600.e1. Available:https://doi.org/10.1016/B978-0-7020-5101-2.00044-3

Orjih AU. Heme polymerase activity and the stage specificity of antimalarial action of chloroquine. J. Pharmacol. Exp. Ther. 1997;282:108-112.

Chemotherapy of malaria and resistance to antimalarials. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1973;529:1-121.

Guidelines for the treatment of malaria. Geneva: World Health Organisation; 2006.

Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infection: An old drug against today’s diseases? Lancet Infect. Dis. 2003; 3:722-727. DOI: 10.1016/s1473-3099(03)00806-5

Rolain JM, Colson P, Raoult D. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int. J. Antimicrob. Agents. 2007;30:297-308. DOI: 10.1016/j.ijantimicag.2007.05.015

Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269–271. DOI:10.1038/s41422-020-0282-0

Principi N, Esposito S, Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infect. Dis. 2020. DOI:10.1016/S1473-3099(20)30296-6

Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: An old drug against today's diseases? Lancet Infect Dis. 2003; 3:722-727. DOI: 10.1016/s1473-3099(03)00806-5

Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14:72-73. DOI: 10.5582/bst.2020.01047.

CHEN Jun, LIU Danping, LIU Li, LIU Ping, XU Qingnian, XIA Lu, LING Yun, HUANG Dan, SONG Shuli, ZHANG Dandan, QIAN Zhiping, LI Tao, SHEN Yinzhong, LU Hongzhou. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci). 2020;49:0-0.

Gautret P, Lagiera JC, Parolaa P, Hoanga VT, Meddeba L, Mailha M et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open label non-randomized clinical trial. Int J Antimicrob Agents. 2020;105949. DOI: 10.1016/j.ijantimicag.2020.105949

Dabbagh MF, Aurora L, D'Souza P, Weinmann AJ, Bhargava P, Basir MB. Cardiac Tamponade Secondary to COVID-19. JACC Case Rep; 2020. DOI:10.1016/j.jaccas.2020.04.009

Fontana F, Alfano G, Mori G et al. Covid-19 pneumonia in a kidney transplant recipient successfully treated with Tocilizumab and Hydroxychloroquine. Am J Transplant; 2020. DOI:10.1111/ajt.15935

Beauverd Y, Adam Y, Assouline B, Samii K. COVID-19 infection and treatment with hydroxychloroquine cause severe haemolysis crisis in a patient with glucose-6-phosphate dehydrogenase deficiency. Eur J Haematol; 2020. DOI:10.1111/ejh.13432

Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N, Zarychanski R, Kelly LE, Schwartz IS, Hullsiek KH. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. The New England journal of medicine. 2020;383(6):517–525. Available:https://doi.org/10.1056/NEJMoa2016638

Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo L, Veiga VC, Avezum A, Damiani LP, Marcadenti A, Kawano-Dourado L, Lisboa T, Junqueira D, De Barros E Silva, P Tramujas L, Abreu-Silva EO, Laranjeira, LN, Soares AT, Echenique LS, Pereira AJ, Freitas F, Gebara O. Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. The New England journal of medicine. 2020;383(21):2041–2052. Available:https://doi.org/10.1056/NEJMoa2019014

De Clercq E. New nucleoside analogues for the treatment of hemorrhagic fever virus infections. Chem Asian J. 2019;14: 3962–3968. DOI:10.1002/asia.201900841

De Wit E, Feldmann F, Cronin J et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A; 2020;117: 6771–6776. DOI: 10.1073/pnas.1922083117

Mulangu S, Dodd LE, Davey RT et al. A Randomized, controlled trial of ebola virus disease therapeutics. N Engl J Med. 2019; 381:2293–2303. DOI:10.1056/NEJMoa1910993

Lo MK, Jordan R, Arvey A et al. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep. 2017;7:43395. DOI: 10.1038/srep43395

Tchesnokov EP, Feng JY, Porter DP, Götte M, Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir. Viruses. 2019; 11:326. DOI: 10.3390/v11040326

Dong L, Hu S, Gao L. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14: 58–60. DOI:10.5582/ddt.2020.01012

Agostini ML, Andres EL, Sims AC et al. 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

Sheahan TP, Sims AC, Leist SR et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir and interferon beta against MERS-CoV. Nat Commun. 2020; 11:222. DOI:10.1038/s41467-019-13940-6

Cao YC, Deng QX, Dai SX, Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence. Travel medicine and infectious disease. 2020; 101647. Advance online publication. Available:https://doi.org/10.1016/j.tmaid.2020.101647

Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci. 2020; 248:117477. DOI:10.1016/j.lfs.2020.117477

Gao Y, Yan L, Huang Y et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science; 2020. DOI:10.1126/science.abb7498

Holshue ML, DeBolt C, Lindquist S et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020; 382:929–936. DOI: 10.1056/NEJMoa2001191

Hillaker E, Belfer JJ, Bondici A, Murad H, Dumkow LE. Delayed Initiation of Remdesivir in a COVID-19 positive patient. Pharmacotherapy; 2020. DOI:10.1002/phar.2403

Grein J, Ohmagari N, Shin D et al. Compassionate use of Remdesivir for patients with severe Covid-19. N Engl J Med; 2020. DOI:10.1056/NEJMoa2007016

Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis. 2020. DOI:10.1016/j.tmaid.2020.101615

Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G. ACTT-1 study group members. Remdesivir for the treatment of Covid-19 - Final report. The New England journal of medicine. 2020;383(19):1813–1826. Available:https://doi.org/10.1056/NEJMoa2007764

Chan JF, Yao Y, Yeung ML et al. Treatment with Lopinavir/Ritonavir or Interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis. 2015;212:1904–1913. DOI: 10.1093/infdis/jiv392

Abou-El-Nag IF, El Kerdany ED, Mady RF, Shalaby TI, Zaytoun EM. The effect of lopinavir/ritonavir and lopinavir/ritonavir loaded PLGA nanoparticles on experimental toxoplasmosis. Parasitol Int. 2017; 66:735–747. DOI: 10.1016/j.parint.2017.08.007

Arabi YM, Alothman A, Balkhy HH et al. Treatment of middle east respiratory syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): Study protocol for a randomized controlled trial. Trials. 2018;19:81. DOI:10.1186/s13063-017-2427-0

Flexner C. HIV-Protease inhibitors. N Engl J Med. 1998; 338:1281-93. DOI: 10.1056/NEJM199804303381808

Chandwani A, Shuter J, Lopinavir/ritonavir in the treatment of HIV-1 infection: A review. Ther Clin Risk Manag. 2008;4:1023-1033. DOI: 10.2147/tcrm.s3285

Van der Laan LE, Garcia-Prats AJ, Schaaf HS et al. Pharmacokinetics and Drug-Drug Interactions of lopinavir-ritonavir administered with first- and second-line antituberculosis drugs in HIV-infected children treated for multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2018; 62:e00420-17. DOI: 10.1128/AAC.00420-17

Lu H, Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020;14:69–71. DOI: 10.5582/bst.2020.01020

Deng L, Li C, Zeng Q et al. Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: A retrospective cohort study. J Infect. S0163-2020;4453:30113-4. DOI:10.1016/j.jinf.2020.03.002

Lim J, Jeon S, Shin HY et al. Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: The application of Lopinavir/Ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT PCR. J Korean Med Sci. 2020;35:e79. DOI: 10.3346/jkms.2020.35.e79

Cao B, Wang Y, Wen D et al. A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020. DOI:10.1056/NEJMoa2001282

Recovery Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet (London, England). 2020;396(10259):1345–1352. Advance online publication. Available:https://doi.org/10.1016/S0140-6736(20)32013-4

Omrani AS, Saad MM, Baig K et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: A retrospective cohort study. Lancet Infect Dis. 2014;14: 1090–1095. DOI: 10.1016/S1473-3099(14)70920-X

Li G, De Clercq E, Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19:149–150. DOI: 10.1038/d41573-020-00016-0

Singh TU, Parida S, Lingaraju MC, Kesavan M, Kumar D, Singh RK. Drug repurposing approach to fight COVID-19. Pharmacol Rep. 2020;72(6):1479-1508.

Van Erp EA, Luytjes W, Ferwerda G et al. Fc-Mediated antibody effector functions during respiratory syncytial virus infection and disease. Front Immunol. 2019;10:548.

Luke TC, Kilbane EM, Jackson JL et al. Meta-analysis: Convalescent blood products for Spanish influenza pneumonia: A future H5N1 treatment? Ann Intern Med. 2006;145(8):599-609.

Lai ST. Treatment of severe acute respiratory syndrome. Eur J Clin Microbiol Infect Dis. 2005;24:583-91.

Soo YO, Cheng Y, Wong R et al. Retrospective comparision of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect 2004;10: 676-78.

Bloch EM, Shoham S, Casadevall A et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020;7:138745. DOI: 10.1172/JCI138745

Tonn T, Corman VM, Johnsen M, Richter A, Rodionov RN, Drosten C, Bornstein SR, Stability and neutralising capacity of SARS-CoV-2-specific antibodies in convalescent plasma. The Lancet. Microbe. 2020;1(2):63. Available:https://doi.org/10.1016/S2666-5247(20)30037-9

Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci USA. 2020;117(17):9490-9496. DOI: 10.1073/pnas.2004168117

Epub 2020 Apr 6. PMID: 32253318; PMCID: PMC7196837.

Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P. PLACID trial collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: Open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020; Oct 22;371:m3939. DOI: 10.1136/bmj.m3939

Erratum in: BMJ. 2020 Nov 3;371:m4232. PMID: 33093056; PMCID: PMC7578662.

Wang C, Liu Z, Chen Z et al. The establishment of reference sequence for SARS-CoV-2 and variation analysis. J Med Virol; 2020. DOI:10.1002/jmv.25762

Vanden Eynde JJ, COVID-19: A Brief Overview of the Discovery Clinical Trial. Pharmaceuticals (Basel). 2020;13: 65. DOI:10.3390/ph13040065

Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A Review [published online ahead of print, 2020 Apr 13]. JAMA. 2020;10:1001 /jama.2020.6019. DOI:10.1001/jama.2020.6019.