Current Status of Multiple Drug Molecules, and Vaccines: An Update in SARS-CoV-2 Therapeutics

Ramesh Kandimalla, Albin John, Chandrika Abburi, Jayalakshmi Vallamkondu, P Hemachandra Reddy, Ramesh Kandimalla, Albin John, Chandrika Abburi, Jayalakshmi Vallamkondu, P Hemachandra Reddy

Abstract

The coronavirus disease of 2019 (COVID-19) is a pandemic disease that has taken the lives of many around the world. It is caused by severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). To date, the USA, Italy, Spain, France, Russia, and the UK have been hit the hardest by the virus. However, death counts are still rising. Some nations have managed to "flatten" the death rate via protective measures such physical distancing, quarantine measures, and therapeutic management. The structure of the SARS-CoV-2 virus comprises of S proteins, M proteins, E proteins, hemagglutinin esterases, nucleocapsid proteins, and a 30-kb RNA genome. Viral proteases cleave these polyproteins and RNA-dependent polymerases replicate the genome. Currently, there are no effective therapies against this new disease. Numerous investigators are developing novel protease inhibitors, some of which have made it into clinical trials. Researchers are also attempting to develop a vaccine. In this review paper, we discuss the latest therapeutic developments against COVID-19. Graphical Abstract.

Keywords: HCQ; Protease inhibitor; Remdesivir; SARS-CoV-2; Vaccines.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7360695/bin/12035_2020_2022_Figa_HTML.jpg
Graphical Abstract
Fig. 1
Fig. 1
Mechanism of action of HCQ, remdesivir, and favipiravir to exacerbate COVID-19: SARS-CoV2 enters into the host cell (AT2) through ACE2 receptors and under goes subsequent stages in endosomes and lysosomes and finally with the help of RNA-dependent polymerase undergoes replication and produces polyproteins (S, M, E, N). HCQ exerts its action at different levels: prevents the entry of SARS-CoV2 into the host cell, glycosylation of host receptors, endosomal acidification, and proteolytic processing. Remdesivir and favipiravir act on RNA-dependent RNA polymerase (RdRp) to prevent replication and translation processes
Fig. 2
Fig. 2
Structure of SARS-CoV2: it depicts spike (S), membrane (M), envelope (E), nucleocapsid (N), and hemagglutinin esterase (HE) and targets for vaccines and drug molecules
Fig. 3
Fig. 3
Structure of drug molecules

References

    1. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, Ma Z, Zhang Y, Shi G, Lam TTY, Wu JT, Gao GF, Cowling BJ, Yang B, Leung GM, Feng Z. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382:1199–1207.
    1. Xiao Y, Pan H, She Q, Wang F, Chen M. Prevention of SARS-CoV-2 infection in patients with decompensated cirrhosis. Lancet Gastroenterol Hepatol. 2020;5:528–529.
    1. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;323(1824):1836. doi: 10.1001/jama.2020.6019.
    1. Wu A, Peng Y, Huang B, et al. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe. 2020;27(325):328.
    1. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nat Med. 2020;26:450–452.
    1. Lotteau V, Teyton L, Peleraux A, Nilsson T, Karlsson L, Schmid SL, Quaranta V, Peterson PA. Intracellular transport of class II MHC molecules directed by invariant chain. Nature. 1990;348:600–605.
    1. Wu SF, Chang CB, Hsu JM, Lu MC, Lai NS, Li C, Tung CH. Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res Ther. 2017;19:183.
    1. van den Borne BE, Dijkmans BA, de Rooij HH, le Cessie S, Verweij CL. Chloroquineand hydroxychloroquine equally affect tumor necrosis factor-alpha interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J Rheumatol. 1997;24:55–60.
    1. Kuznik A, Bencina M, Svajger U, Jeras M, Rozman B, Jerala R. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol (Baltimore, Md : 1950) 2011;186:4794–4804.
    1. Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA, Barton GM. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature. 2008;456:658–662.
    1. Häcker H, Mischak H, Miethke T, Liptay S, Schmid R, Sparwasser T, Heeg K, Lipford GB, Wagner H. CpG-DNA-specific activation of antigen presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J. 1998;17:6230–6240.
    1. Vollmer J, Tluk S, Schmitz C, et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J Exp Med. 2005;202:1575–1585.
    1. An J, Woodward JJ, Sasaki T, Minie M, Elkon KB. Cutting edge: antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase DNA interaction. J Immunol (Baltimore, Md : 1950) 2015;194:4089–4093.
    1. Zhou D, Dai SM, Tong Q (2020) COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. The Journal of antimicrobial chemotherapy. J Antimicrob Chemother:dkaa114. 10.1093/jac/dkaa114
    1. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55:105938.
    1. 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.
    1. Gautret P, Lagier JC, Parola P et al (2020) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents:105949
    1. Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang da xue xue bao Yi xue ban = J Zhejiang Univ Med Sci. 2020;49:215–219.
    1. Lenzer J. Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence. BMJ. 2020;369:m1335. doi: 10.1136/bmj.m1335.
    1. Yi SG, Rogers AW, Saharia A, et al Early experience with COVID-19 and solid organ transplantation at a US high-volume transplant center [published online ahead of print, 2020 Jun 1]. Transplantation. 2020; 10.1097/TP.0000000000003339
    1. Yao X, Ye F, Zhang M, et al (2020) 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). [published online ahead of print, 2020 Mar 9]. Clin Infect Dis. ciaa237. 10.1093/cid/ciaa237
    1. Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA. 2020;323:1897. doi: 10.1001/jama.2020.4742.
    1. Interview with David Juurlink (2020) Coronavirus (COVID-19) update: chloroquine/hydroxychloroquine and azithromycin. JAMA March 24, 2020. Accessed 5 Apr 2020.
    1. Osadchy A, Ratnapalan T, Koren G. Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature. J Rheumatol. 2011;38:2504–2508.
    1. Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, Mourão MPG, Brito-Sousa JD, Baía-da-Silva D, Guerra MVF, Hajjar LA, Pinto RC, Balieiro AAS, Pacheco AGF, Santos JDO, Jr, Naveca FG, Xavier MS, Siqueira AM, Schwarzbold A, Croda J, Nogueira ML, Romero GAS, Bassat Q, Fontes CJ, Albuquerque BC, Daniel-Ribeiro CT, Monteiro WM, Lacerda MVG, for the CloroCovid-19 Team Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3:e208857.
    1. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3:e343.
    1. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS, Yuen KY, HKU/UCH SARS Study Group Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252–256.
    1. de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, van den Hoogen BG, Neyts J, Snijder EJ. Screening of an FDAapproved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58:4875–4884.
    1. Yao TT, Qian JD, Zhu WY, Wang Y, Wang GQ. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-a possible reference for coronavirus disease-19 treatment option. J Med Virol. 2020;92:556–563.
    1. Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Medical Journal = Xianggang yi xue za zhi. 2003;9:399–406.
    1. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382:1787–1799.
    1. De Meyer S, Bojkova D, Cinati J, et al (2020) Lack of antiviral activity of darunavir against SARS-CoV-2. medRxiv 2020: 2020.04.03.20052548
    1. action/Table_of_therapeutics_Appendix_17022020.pdf (accessed on 28 May 2020)
    1. 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;30:26971.
    1. Mentre F, Taburet AM, Guedj J, Anglaret X, Keita S, de Lamballerie X, Malvy D. Dose regimen of favipiravir for Ebola virus disease. Lancet Infect Dis. 2015;15:150–151.
    1. Sissoko D, Laouenan C, Folkesson E, M’Lebing AB, Beavogui AH, Baize S, Camara AM, Maes P, Shepherd S, Danel C, Carazo S, Conde MN, Gala JL, Colin G, Savini H, Bore JA, le Marcis F, Koundouno FR, Petitjean F, Lamah MC, Diederich S, Tounkara A, Poelart G, Berbain E, Dindart JM, Duraffour S, Lefevre A, Leno T, Peyrouset O, Irenge L, Bangoura N’F, Palich R, Hinzmann J, Kraus A, Barry TS, Berette S, Bongono A, Camara MS, Chanfreau Munoz V, Doumbouya L, Souley Harouna, Kighoma PM, Koundouno FR, Réné Lolamou, Loua CM, Massala V, Moumouni K, Provost C, Samake N, Sekou C, Soumah A, Arnould I, Komano MS, Gustin L, Berutto C, Camara D, Camara FS, Colpaert J, Delamou L, Jansson L, Kourouma E, Loua M, Malme K, Manfrin E, Maomou A, Milinouno A, Ombelet S, Sidiboun AY, Verreckt I, Yombouno P, Bocquin A, Carbonnelle C, Carmoi T, Frange P, Mely S, Nguyen VK, Pannetier D, Taburet AM, Treluyer JM, Kolie J, Moh R, Gonzalez MC, Kuisma E, Liedigk B, Ngabo D, Rudolf M, Thom R, Kerber R, Gabriel M, di Caro A, Wölfel R, Badir J, Bentahir M, Deccache Y, Dumont C, Durant JF, el Bakkouri K, Gasasira Uwamahoro M, Smits B, Toufik N, van Cauwenberghe S, Ezzedine K, Dortenzio E, Pizarro L, Etienne A, Guedj J, Fizet A, Barte de Sainte Fare E, Murgue B, Tran-Minh T, Rapp C, Piguet P, Poncin M, Draguez B, Allaford Duverger T, Barbe S, Baret G, Defourny I, Carroll M, Raoul H, Augier A, Eholie SP, Yazdanpanah Y, Levy-Marchal C, Antierrens A, van Herp M, Günther S, de Lamballerie X, Keïta S, Mentre F, Anglaret X, Malvy D, JIKI Study Group Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof of-concept trial in Guinea. PLoS Med. 2016;13:e1001967.
    1. Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life threatening RNA virus infections. Pharmacol Ther. 2020;209:107512.
    1. Chinello P, Petrosillo N, Pittalis S, Biava G, Ippolito G, Nicastri E. QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient. PLoS Negl Trop Dis. 2017;11:e0006034.
    1. Kumagai Y, Murakawa Y, Hasunuma T, Aso M, Yuji W, Sakurai T, Noto M, Oe T, Kaneko A. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. Int J Clin Pharmacol Ther. 2015;53:866–874.
    1. Chen C, Zhang Y, Huang J, et al (2020) Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. medRxiv 2020.03.17.20037432
    1. Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, Neville S, Carra E, Lew W, Ross B, Wang Q, Wolfe L, Jordan R, Soloveva V, Knox J, Perry J, Perron M, Stray KM, Barauskas O, Feng JY, Xu Y, Lee G, Rheingold AL, Ray AS, Bannister R, Strickley R, Swaminathan S, Lee WA, Bavari S, Cihlar T, Lo MK, Warren TK, Mackman RL. Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J Med Chem. 2017;60:1648–1661.
    1. Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis. 2020;2020:101615.
    1. World Health Organization (2018) WHO R&D blueprint: ad-hoc expert consultation on clinical trials for Ebola therapeutics. Published October 2018. Accessed 20 May 2020. experimentaltherapeutics.pdf
    1. Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: a single center experience. J Med Virol. 2020;92:814–818. doi: 10.1002/jmv.25801.
    1. Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 2020;18:164.
    1. Krammer F, Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov. 2015;14:167–182.
    1. Amanat F, Krammer F. SARS-CoV-2 vaccines: status report. Immunity. 2020;52:583–589.
    1. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM, Zheng JJ, Xu L, Holmes EC, Zhang YZ. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579:265–269.
    1. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273.
    1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W, China Novel Coronavirus Investigating and Research Team A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733.
    1. Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, Zhang Q, Shi X, Wang Q, Zhang L, Wang X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581:215–220.
    1. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367:1260–1263.
    1. Lan L, Xu D, Ye G, Xia C, Wang S, Li Y, Xu H. Positive RT-PCR test results in patients recovered from COVID-19. JAMA. 2020;323:1502–1503.
    1. Callow KA, Parry HF, Sergeant M, Tyrrell DA. The time course of the immune response to experimental coronavirus infection of man. Epidemiol Infect. 1990;105:435–446.
    1. Jiang H-W, Li Y, Zhang H-N, et al (2020) Global profiling of SARS-CoV-2 specific IgG/IgM responses of convalescents using a proteome microarray. medRxiv 2020: 2020.03.20.20039495
    1. Wu F, Wang A, Liu M, et al (2020) Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv 2020: 2020.03.30.20047365
    1. (accessed on May 28th, 2020)
    1. Zhu FC, Li YH, Guan XH et al (2020, 2020) Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open label, non-randomised, first-in-human trial. Lancet (London, England). 10.1016/S0140-6736(20)31208-3
    1. Neumann-Böhme S, Varghese NE, Sabat I, Barros PP, Brouwer W, van Exel J, Schreyögg J, Stargardt T (2020) Once we have it, will we use it? A European survey on willingness to be vaccinated against COVID-19 [published online ahead of print, 2020 Jun 26]. Eur J Health Econ:1–6. 10.1007/s10198-020-01208-6

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