Revisiting potential druggable targets against SARS-CoV-2 and repurposing therapeutics under preclinical study and clinical trials: A comprehensive review

Abstract

Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the most contagious diseases in human history that has already affected millions of lives worldwide. To date, no vaccines or effective therapeutics have been discovered yet that may successfully treat COVID-19 patients or contain the transmission of the virus. Scientific communities across the globe responded rapidly and have been working relentlessly to develop drugs and vaccines, which may require considerable time. In this uncertainty, repurposing the existing antiviral drugs could be the best strategy to speed up the discovery of effective therapeutics against SARS-CoV-2. Moreover, drug repurposing may leave some vital information on druggable targets that could be capitalized in target-based drug discovery. Information on possible drug targets and the progress on therapeutic and vaccine development also needs to be updated. In this review, we revisited the druggable targets that may hold promise in the development of the anti-SARS-CoV-2 agent. Progresses on the development of potential therapeutics and vaccines that are under the preclinical studies and clinical trials have been highlighted. We anticipate that this review will provide valuable information that would help to accelerate the development of therapeutics and vaccines against SARS-CoV-2 infection.

Keywords: COVID-19; clinical trial; drug repurposing; drug targets; therapeutics; vaccines.

FIGURE 1

(a) A schematic diagram of the SARS‐CoV‐2 (modified from Du et al., 2009). S, Spike protein; E, envelope protein; single‐stranded positive‐sense viral RNA, and M, membrane protein are depicted. (b) A schematic diagram of the SARS‐CoV‐2 life cycle in a host cell (modified from Du et al., 2009). (1) Virus entry into the host cell via ACE2 or endocytosis, (2) Release of RNA from endosome, (3) Proteolytic cleavage of polyprotein, (4) synthesis of genomic and subgenomic RNA, (5) structural protein synthesis and maturation, and (6) Assembly of viral particles and mature viral particle. 3CLpro, chymotrypsin‐like protease; ACE2, Angiotensin‐converting enzyme 2; E, Envelope protein; M, membrane protein; N, nucleocapsid; PLpro, papain‐like protease; S, Spike protein; TMPRSS2, Transmembrane protease, serine 2

FIGURE 2

A schematic diagram indicating the potential drug targets and drugs on viral replication processes. (1) ACE2 and spike complex inhibitors: Azithromycin and Chloroquine, interrupt in ACE2 and S protein complex formation; (2) TMPRSS2 inhibitor: Camostat Mesylate blocks cleavage and activation of the S protein; (3) Targeting endosomes: chloroquine and its derivatives increase pH and inhibit viral RNA release from endosomes; (4) Targeting proteases: ASC09F, Oseltamivir, Ritonavir, Oseltamivir, Oseltamivir, Lopinavir inhibit proteases thereby inhibit viral replication; (5) Targeting RdRp: Favipiravir, Remdesivir, and Ribavirin block RdRp and cause premature termination of RNA synthesis; (6) Targeting Spike: Monoclonal antibody, Arbidol, and convalescent plasma block spike protein which results into binding interruption with ACE2; (7) Targeting host immune system: activated host immune system can block virus propagation as well as recover body from the adverse effects posed by viruses

FIGURE 3

Possible strategies for vaccine design and development. (a) Attenuated Virus Vaccine: Attenuation of the virus by chemicals, such as formaldehyde, or heat; (b) Nucleic acid vaccine: Contains the genetic material only; (c) Viral vector vaccine: A genetically modified virus that can generate SARS‐CoV‐2 proteins in the body; (d) Protein‐based vaccine: protein shells or fragments of proteins that imitate the virus's outer coat