The Open Virology Journal




ISSN: 1874-3579 ― Volume 14, 2020
PERSPECTIVE ARTICLE

Strategies and Challenges to Develop Therapeutic Candidates against COVID-19 Pandemic



Rohit Bhatia1, *, Subrahmanya S Ganti1, Raj Kumar Narang2, Ravindra Kumar Rawal3
1 Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab-142001, India
2 Department of Pharmaceutics, ISF College of Pharmacy, Ferozepur G.T. Road, Moga-142 001, Punjab, India
3 Department of Chemistry, Maharishi Markandeshwar (Deemed to be University), Mullana-133207, Haryana, India

Abstract

Keywords: Pandemic , COVID-19 , Therapeutic candidates , Epidemics , Respiratory syndrome , SARS-CoV .


Article Information


Identifiers and Pagination:

Year: 2020
Volume: 14
First Page: 16
Last Page: 21
Publisher Id: TOVJ-14-16
DOI: 10.2174/1874357902014010016

Article History:

Received Date: 07/5/2020
Revision Received Date: 07/7/2020
Acceptance Date: 08/8/2020
Electronic publication date: 20/10/2020
Collection year: 2020

© 2020 Bhatia et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab-142001, India; Tel: 8628885561; E-mail: bhatiarohit5678@gmail.com





1. PERSPECTIVE

The terrible story of the coronavirus disease (COVID-19) needs no introduction in the present hour. It is evident that viral diseases have always appeared as a mystery and are the fatal ailments in human beings. The history justifies this fact of viral epidemics, such as SARS-CoV prevailed during 2002-2003, H1N1 during 2009, MERS-CoV in 2012 and the most dreadful COVID-19 from December 2019 to till date [1]. This ailment has emerged as a wonderstruck and put the whole world in worry and confusion. According to the latest WHO situation report-90, up to 29th April, there are 30,18,681 total confirmed cases of COVID-19 and approximately 2,07,973 people had lost their lives all over the world [2]. Coronaviruses (CoVs) are the major microorganisms causing fatal respiratory disease outbreaks worldwide. These constitute a large group of single-stranded RNA viruses and can be isolated from a wide variety of animal species [3,4]. CoVs have an appearance like a crown (coronam a Latin term) due to the presence of glycoprotein spikes on its envelope [5]. To date, seven human coronaviruses (HCoVs) have been identified. The common HCoVs are HCoV-OC43, and HCoV-HKU1; HCoV-229E and HCoV-NL63 (αCoVs), which are responsible for the common cold and lower extent of upper respiratory disorders. Other HCoVs are severe acute respiratory syndrome causing coronavirus (SARS-CoV), SARS-CoV-2 and the Middle East respiratory syndrome causing the coronavirus (MERS-CoV), which can cause epidemics with severe respiratory manifestations [6].

2. PATHOGENESIS OF COVID-19

The progression of COVID-19 can be divided into three major stages: Asymptomatic stage, upper airway response stage and progression to Acute Respiratory Distress Syndrome (ARDS) [7Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J 2020; 55(4): 2000607.
[http://dx.doi.org/10.1183/13993003.00607-2020] [PMID: 32269085]
]. The first stage is regarded as the stage after 1-2 days of the infection. In this, SARS-CoV-2 enters the nasal cavity and gets bounded to epithelial cells there with the help of the ACE2 receptor [8Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virol 2020; 94(7): e00127-20.
[http://dx.doi.org/10.1128/JVI.00127-20] [PMID: 31996437]
, 9Hoffmann M, Kleine-Weber H, Schroeder S, et al. 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.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
]. When it enters inside the cell, the viral RNA gets released into the cytoplasm of the cell where translation occurs, leading to the formation of proteins and replication [10Perlman S, Netland J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 2009; 7: 439e450.
[http://dx.doi.org/10.1038/nrmicro2147]
]. It starts replicating and ciliated cells are believed to be infected here [11Sims AC, Baric RS, Yount B, Burkett SE, Collins PL, Pickles RJ. Severe acute respiratory syndrome coronavirus infection of human ciliated airway epithelia: Role of ciliated cells in viral spread in the conducting airways of the lungs. J Virol 2005; 79(24): 15511-24.
[http://dx.doi.org/10.1128/JVI.79.24.15511-15524.2005] [PMID: 16306622]
]. It is the local propagating stage, viral loads are low, and the infection can be detected by using nasal swabs. The innate immune response at this stage is low. In the next few days, the virus starts propagating towards lower respiratory track along with conducting organs and the extent of innate immune response gets elevated. At this stage, the sputum analysis represents a virus and other markers of innate immunity. It confirms the manifestation of COVID-19 disease. The level of cytokine CXCL10 can be predicted for clinical studies [12Tang NL, Chan PK, Wong CK, et al. Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin Chem 2005; 51(12): 2333-40.
[http://dx.doi.org/10.1373/clinchem.2005.054460] [PMID: 16195357]
]. The infected epithelial cells yield beta and lambda interferons [13Hancock AS, Stairiker CJ, Boesteanu AC, et al. Transcriptome analysis of infected and bystander type 2 alveolar epithelial cells during influenza A virus infection reveals in vivo Wnt pathway downregulation. J Virol 2018; 92(21): e01325-18.
[http://dx.doi.org/10.1128/JVI.01325-18] [PMID: 30111569]
]. CXCL10 is a gene that is highly responsive to interferons in alveolar type II cell response in the case of SARS-CoV and is also a disease marker for SARS [14Qian Z, Travanty EA, Oko L, et al. Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus. Am J Respir Cell Mol Biol 2013; 48(6): 742-8.
[http://dx.doi.org/10.1165/rcmb.2012-0339OC] [PMID: 23418343]
-16Rockx B, Baas T, Zornetzer GA, et al. Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. J Virol 2009; 83(14): 7062-74.
[http://dx.doi.org/10.1128/JVI.00127-09] [PMID: 19420084]
]. It was evident that for about 80% of infected people, the disease was mild and limited only to the upper respiratory region. The rest of about 20% sufferers, unfortunately, go to severe stage 3 and are associated with respiratory infiltrates. The virus enters the lungs and alveolar type II cells and liesin peripheral or pleural sites [17Wu J, Wu X, Zeng W, et al. Chest CT findings in patients with corona virus disease 2019 and its relationship with clinical features. Invest Radiol 2020. in press]. A large population of viruses gets released and cells undergo apoptosis and ultimately die. The results are the development of pulmonary toxin, which invades the adjacent cells leading to secondary pathway initiation foe regeneration of epithelial cells [18Kumar PA, Hu Y, Yamamoto Y, et al. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 2011; 147(3): 525-38.
[http://dx.doi.org/10.1016/j.cell.2011.10.001] [PMID: 22036562]
]. It is reported that these manifestations led to alveolar damage with the evident presence of fibrin rich membranes and giant cells [19Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8(4): 420-2.
[http://dx.doi.org/10.1016/S2213-2600(20)30076-X] [PMID: 32085846]
]. To recover at this stage, a vigorous immune response is required with extremely rapid epithelial regeneration. The elder people are at very much higher risk at this stage due to low immune response and slow epithelial regeneration. This pathogenesis is not still 100% clear and may take few more months to resolve the unclear mechanisms.

A huge number of research groups from all parts of the world are continuously working in order to develop therapeutic agents against COVID-19, but no vaccine or therapeutic candidate has been developed to date. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a signi- ficant number of potential drug targets. These targets include spike protein (S), an envelope protein (E), membrane protein (M), protease, nucleocapsid protein, hemagglutinin esterase, helicase and several Nonstructural Proteins (NSPs) [20Prajapat M, Sarma P, Shekhar N, et al. Drug targets for corona virus: A systematic review. Indian J Pharmacol 2020; 52(1): 56-65.
[http://dx.doi.org/10.4103/ijp.IJP_115_20] [PMID: 32201449]
-22Wang H, Xue S, Yang H, Chen C. Recent progress in the discovery of inhibitors targeting coronavirus proteases. Virol Sin 2016; 31(1): 24-30.
[http://dx.doi.org/10.1007/s12250-015-3711-3] [PMID: 26920707]
] which are currently being focussed for drug discovery and drug development. The drugs or vaccines which are currently under investigation or in clinical trials against COVID-19 have been depicted in (Table 1).

Table 1
Drugs under investigation against COVID-19.


Various treatment strategies to treat and manage the SARS-CoV-2 infection have been summarized in the following sections.

3. DEVELOPMENT OF ANTIBODIES TO SARS-COV-2

It is well known that the entry of coronavirus is mediated by S protein followed by the release of viral nucleocapsid inside the cell for the purpose of replication [45Tortorici MA, Veesler D. Structural insights into coronavirus entry. Adv Virus Res 2019; 105: 93-116.
[http://dx.doi.org/10.1016/bs.aivir.2019.08.002] [PMID: 31522710]
]. S protein also causes symplasm formation between normal receptor-bearing cells and infected cells around them. Targeting the surface of SARS-CoV-2 with a neutralizing antibody has been looked for thoroughly by various research groups in order to provide a passive immunity [46Casadevall A, Pirofski LA. The Ebola epidemic crystallizes the potential of passive antibody therapy for infectious diseases. PLoS Pathog 2015; 11(4): e1004717.
[http://dx.doi.org/10.1371/journal.ppat.1004717] [PMID: 25905897]
]. The gene synthesis can be carried out in a laboratory considering the expression of S protein as an immunogen utilizing the recently launched genome sequence of SARS-CoV-2 (GenBank: MN908947.3). Traditional methods using experimental animals are also available but they are too slow as per the current situation of this pandemic. Instead, faster methods such as the utilization of phage library or yeast display library to express specific antibodies can be utilized for viral neutralization [47Shin YW, Chang KH, Hong GW, et al. Selection of vaccinia virus-neutralizing antibody from a phage-display human-antibody library. J Microbiol Biotechnol 2019; 29(4): 651-7.
[http://dx.doi.org/10.4014/jmb.1812.12024] [PMID: 30856707]
, 48Keck ZY, Wang Y, Lau P, Foung SKH. Isolation of HCV neutralizing antibodies by yeast display. Methods Mol Biol 2019; 1911: 395-419.
[http://dx.doi.org/10.1007/978-1-4939-8976-8_27] [PMID: 30593641]
]. The challenges in this task are rigorous testing in cell culture labs, animal models, information from other CoV species and use of a cocktail of antibodies. For quick production of antibodies, lead therapeutic candidates can be utilized for protein expression in bacteria, yeast or insect cells [49Tripathi NK, Shrivastava A. Recent developments in bioprocessing of recombinant proteins: Expression hosts and process development. Front Bioeng Biotechnol 2019; 7: 420.
[http://dx.doi.org/10.3389/fbioe.2019.00420] [PMID: 31921823]
]. A much promising approach for producing neutralizing antibodies can be immunizing sheep, goat, cow or large animals with the SARS-CoV-2 proteins followed by purification of antibodies from the animals [50Schmidt R, Beltzig LC, Sawatsky B, et al. Generation of therapeutic antisera for emerging viral infections. NPJ Vaccines 2018; 3: 42-10.
[http://dx.doi.org/10.1038/s41541-018-0082-4] [PMID: 30323953]
]. The challenge associated with the use of large animals is that there is no guarantee that they will produce neutralizing antisera or not. Another complication may be the human immune response against foreign antibodies.

4. UTILIZING OLIGONUCLEOTIDES AGAINST SARS-COV-2

The RNA genome of the SARS-CoV-2 could be targeted against COVID-19. RNA genome sequence (GenBank: MN908947.3) for this has been recently published and it can be targeted through small interfering RNAs or antisense oligonu- cleotides [51Qureshi A, Tantray VG, Kirmani AR, Ahangar AG. A review on current status of antiviral siRNA. Rev Med Virol 2018; 28(4): e1976.
[http://dx.doi.org/10.1002/rmv.1976] [PMID: 29656441]
]. But the challenging task in this approach is to deliver oligonucleotides into the lungs. Another complication associated with this strategy is the non-availability of RNA sequence domains of SARS-CoV-2. Advancements in lipid nanoparticle-based drug delivery systems can deliver into the lungs but only up to a limited extent [52Youngren-Ortiz SR, Gandhi NS, España-Serrano L, Chougule MB. Aerosol delivery of siRNA to the lungs. Part 1: Rationale for gene delivery systems. Kona 2016; 33: 63-85.
[http://dx.doi.org/10.14356/kona.2016014] [PMID: 27081214]
]. But if it becomes possible to deliver small RNAs or antisense oligonucleotides even up to 25% of epithelial cells, it may lead to great success for traditional gene therapy. The need of the hour is to discover the gene homology of SARS-CoV-2 and solve it for future drug development.

5. UTILIZING RECOVERED PATIENT SERA

Another promising and simple approach is the transfer of passive antibodies from the serum of a patient recovered from COVID-19 to treat a suffering patient. These polyclonal antibodies neutralize the virus and can prevent the possibility of a new infection. The cured patients can donate their plasma, which can be transfused to the suffering patient [53Mire CE, Geisbert JB, Agans KN, et al. Passive immunotherapy: Assessment of convalescent serum against ebola virus makona infection in nonhuman primates. J Infect Dis 2016; 214(Suppl. 3): S367-74.
[http://dx.doi.org/10.1093/infdis/jiw333] [PMID: 27571900]
, 54Marano G, Vaglio S, Pupella S, et al. Convalescent plasma: New evidence for an old therapeutic tool? Blood Transfus 2016; 14(2): 152-7.
[PMID: 26674811]
]. The challenging task in this approach is variability in the sera of cured and infected individuals. Although exponential prevalence of this disease may retard the scope of this therapy it still should be considered as an important strategy in the field of transfusion medicines.

6. DEVELOPMENT OF ACE2 BINDING ANTIBODIES

Administration of antibodies that can bind and block the action of ACE2 could be a significant approach to prevent the prevalence of COVID-19 infection. This strategy has been proved experimentally against SARS entry and replication [55Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450-4.
[http://dx.doi.org/10.1038/nature02145] [PMID: 14647384]
]. Although no sequence of ACE2 genome is published, still monoclonal antibodies exist and hybridoma sequences can be cloned only in a few days. It is not concerned with the viral escape from the ACE2 binding antibody unlike the approaches against S protein [56Kruse RT. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China version 2; peer review: 2 approved. F1000Research 2020; 9: 72.]. The limitation of this approach is that other ACE2 receptors in different locations will also get inhibited. Also, the dose to block the ACE2 receptor in different organs of the body is not known. Another compli- cation is turnover number of the ACE2 receptor, which will greatly influence the effect of the administered antibody. This issue can be resolved by increasing the concentration of ACE2 antagonists at the site of infection in the lungs via nebulization technique. Another unfortunate possibility is that direct binding to ACE2 may cause lung injury or may alter the physiology of the lungs.

7. DEVELOPMENT OF ANTIBODY LIKE MOLECULE AGAINST ACE2

Beyond developing antibodies, design and development of antibody-like therapeutic candidate against ACE2 is a much more promising approach which will directly bind and block ACE2. The validity of this approach has already been supported by literature where SARS virus was blocked from infecting cells utilizing soluble ACE2 [57Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target. Intensive Care Med 2020; 46(4): 586-90.
[http://dx.doi.org/10.1007/s00134-020-05985-9] [PMID: 32125455]
]. The reported affinity of soluble ACE2 for the SARS S protein was 1.70 nM, which is comparable to the affinities of monoclonal antibodies. The life span of the circulating molecule can be increased by converting soluble ACE2 into immunoadhesin format by fusing with the immunoglobulin Fc domain (ACE2-Fc) [58Sui J, Li W, Murakami A, et al. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci USA 2004; 101(8): 2536-41.
[http://dx.doi.org/10.1073/pnas.0307140101] [PMID: 14983044]
]. Using ACE2 as SARS-CoV-2 neutralizing agent is advan- tageous because it can directly treat pneumonia patho- physiology. The advanced therapy suggested that the adminis- tration of recombinant ACE2 has significantly improved the acute lung injury by reducing angiotensin II levels by successive attachment of hormones to its 1a type receptor. Due to such excellent clinical abilities, recombinant ACE2 was moved to clinical trials where it revealed significant results. The limitation of ACE2-Fc therapy is that elevated extracellular levels of ACE2 in body may lead to undesirable effects. Another important outcome is that receptor targeting through an antibody can direct SARS-CoV-2 towards infecting Fc receptor-positive cells which has the capability to neutralize the antibodies. But this aspect is unclear and more clinical data is required to reveal the undiscovered mechanisms.

8. REPURPOSING OF PREVIOUSLY APPROVED ANTI-VIRAL DRUGS

Previously approved anti-HIV drugs can be repurposed for their efficacy against SARS-CoV-2 by focussing their inhibi- tory potentials against SARS-CoV-2 target proteins. Therefore drug repurposing is an attractive approach to the researchers, medicinal chemists, clinicians and drug developers in the present situation [59Dyall J, Coleman CM, Hart BJ, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014; 58(8): 4885-93.
[http://dx.doi.org/10.1128/AAC.03036-14] [PMID: 24841273]
]. Drug repurposing is a technique for utilization of the therapeutic value of an existing drug by focusing on infections other than that for which it was initially proposed [60Bhatia R, Narang RK, Rawal RK. Repurposing of RdRp Inhibitors against SARS-CoV-2 through Molecular Docking Tools. Coronaviruses 2020; 1: 1-9.
[http://dx.doi.org/10.2174/2666796701999200617155629]
]. Several drugs have already been repurposed in order to develop a suitable therapeutic candidate against COVID-19. The repurposed drugs include Lopinavir, Ritonavir, Darunavir (against protease); Remdesivir, Ribavirin, Gallidesivir, Penciclovir (against RNA dependent RNA polymerase); Baloxavir (against endonuclease), chloroquine (against ACE2) and Baricitinib (against JAK kinase) [61Liu C, Zhou Q, Li Y, et al. Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent Sci 2020; 6(3): 315-31.
[http://dx.doi.org/10.1021/acscentsci.0c00272] [PMID: 32226821]
]. Most of the repurposed drugs have cleared phase I trials (Table 1), have low risk of failure as well as a very small investment. This approach is able to facilitate great clinical developments at a very low cost. Drug repurposing sometimes may come into light through chance observations, but target based repurposing is based on a thorough understanding of molecular mechanisms or cellular events [62Pizzorno A, Padey B, Terrier O, Rosa-Calatrava M. Drug repurposing approaches for the treatment of influenza viral infection: Reviving old drugs to fight against a long-lived enemy. Front Immunol 2019; 10: 531.
[http://dx.doi.org/10.3389/fimmu.2019.00531] [PMID: 30941148]
, 63Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 2004; 3(8): 673-83.
[http://dx.doi.org/10.1038/nrd1468] [PMID: 15286734]
]. The repurposed drug may or may not work through the same target or mechanism for which it was previously approved. Many recent reports are there where researchers have carried out drug repurposing by targeting on different-different receptors or biomolecules. Hobartner et al. have carried out repurposing of antiviral drug tenofovir for orthogonal RNA catalyzed labeling of RNA [64Maghami MG, Dey S, et al. Repurposing antiviral drugs for orthogonal RNA catalyzed labeling of RNA 2020.]. Sun et al. carried out drug repurposing of pyrimidine analogs as potent antiviral compounds against human enterovirus A71 infection with potential clinical applications [65Sun J, Yogarajah T, Lee RCH, et al. Drug repurposing of pyrimidine analogs as potent antiviral compounds against human enterovirus A71 infection with potential clinical applications. Sci Rep 2020; 10(1): 8159.
[http://dx.doi.org/10.1038/s41598-020-65152-4] [PMID: 32424333]
]. Bhatia et al. have reported repurposing of RdRp inhibitors against SARS-CoV-2 through molecular docking tools with promising results [60Bhatia R, Narang RK, Rawal RK. Repurposing of RdRp Inhibitors against SARS-CoV-2 through Molecular Docking Tools. Coronaviruses 2020; 1: 1-9.
[http://dx.doi.org/10.2174/2666796701999200617155629]
]. Zhou et al. has carried out network based repurposing of drugs against SARS-CoV-2 and screened out 16 repurposable drugs, including melatonin, quinacrine, colchicine, mercaptopurine, irbesartan etc [66Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov 2020; 6: 14.
[http://dx.doi.org/10.1038/s41421-020-0153-3] [PMID: 32194980]
]. Another work was put forward by Singh et al. where they screened out a library of 123 drugs and isolated inhibitors (Raltegravir, Paritaprevir, Bictegravir and Dolute- gravir) of 3CL pro and ribose methyltransferase through repurposing approach [67Khan RJ, Kumar JR, et al. Targeting novel coronavirus 2019: A systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2′-O-ribose methyl- transferase. ChemRxiv 2020.
[http://dx.doi.org/10.26434/chemrxiv.11888730.v1]
]. Kang et al. identified the SARS-CoV-2 3C like protein inhibitory potentials of atazanavir (anti-HIV drug) by utilizing Molecule Transformer-Drug Target Interaction (MT-DTI) for repurposing [68Beck BR, Shin B, Choi Y, Park S, Kang K. Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model. Comput Struct Biotechnol J 2020; 18: 784-90.
[http://dx.doi.org/10.1016/j.csbj.2020.03.025] [PMID: 32280433]
]. In another report, Yelekci et al. have utilized the drug repurposing approach by targeting 3CL hydrolases and proteases of SARS-CoV-2. They screened out talampicillin, lurasidone, rubitecan and lopra- zolam as potential inhibitors of these enzymes through molecular modelling tools [69Elmezayen AD, Al-Obaidi A, Şahin AT, Yelekçi K. Drug repurposing for coronavirus (COVID-19): In silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes. J Biomol Struct Dyn 2020; 1-13.
[http://dx.doi.org/10.1080/07391102.2020.1758791] [PMID: 32306862]
]. Beyond these reports, many others are available in the literature and continuous work is in progress utilizing this drug repurposing approach.

The challenge associated with drug repurposing is the inadequate efficacy of single therapeutic candidate. Another complication associated with this approach is to search and analyze the huge amount of previously reported data to make efficient and effective use against a new indication. The complex/unclear events of the pathophysiology of SARS-CoV-2 also offer a great challenge to select a candidate for repurposing.

CONCLUSION

Although there is continuous work in progress in some of the above mentioned approaches, but there is still no drug/vaccineavailable to treat COVID-19. Drug repurposing offers an economical and rapid strategy to discover a potential therapeutic agent in the current hectic situation. This compilation may be helpful to the researchers, drug developers and health agencies to look into the matter and work against the possible targets to develop a therapeutic candidate against COVID-19.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGMENTS

Declared none.

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