Update on Antiviral Strategies Against COVID-19: Unmet Needs and Prospects

Abstract

By December 2020, the COVID-19 pandemic had caused more than 74 million confirmed cases and 1.6 million related deaths around the world. However, only a few drugs have been approved in certain areas and for use in conditional patients, and the vaccine candidates were only recently approved or authorized for emergency use without being fully implemented worldwide, suggesting that we are yet to reach effective control of the current outbreak as its uninhibited transmission continues precariously. Over the past few months, several therapeutic candidates have been proven ineffective in large clinical trials, while some other agents exhibited promising preliminary results. Meanwhile, the investigation of SARS-CoV-2-specific antivirals is underway. Despite still being preclinical, these agents could be beneficial for the long-term control of COVID-19 and deserve more research focus. In this article, we update the current status of therapeutic candidates that have been examined for COVID-19 management, including the virus-targeting inhibitors and host-targeting agents, with their antiviral efficacy in vitro, in vivo, and in clinical studies. Finally, we highlight the current challenges and future prospect of developing potent therapeutic agents against COVID-19.

Keywords: Coronavirus Disease 2019 (COVID-19); Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2); antiviral; therapeutic; treatment.

Figure 1

SARS-CoV-2 life cycle and antiviral targets. SARS-CoV-2 infection initiates from viral binding to the host cell receptors angiotensin conversion enzyme 2 (ACE2) or CD147. The virus enters the cell either through endocytosis (1a), after which the virus is processed by endosomal proteases and fuses with endosomal membrane, or direct fusion with the plasma membrane in the presence of transmembrane protease serine 2 (TMPRSS2) (1b). Viral genome is released into the cytoplasm (2) and translated to polyprotein 1ab (pp1ab) and polyprotein 1a (pp1a) (3). Pp1a and pp1ab are further cleaved into 16 nonstructural proteins (nsp1-16) by the viral papain like protease (PLpro, nsp3) and 3C-like protease (3CLpro, nsp5) (4). Viral replication is initiated by replication complex (Nsp12-14) and RNA methyltransferase (nsp14, nsp16) in the endoplasmic reticulum (ER) (5). After which, new viral particles are assembled in the ER-Golgi intermediate compartment (ERGIC) (6) followed by spike protein glycosylation and maturation in the Golgi apparatus (7). Finally, progeny virions are released from the host cell through exocytosis (8). Created with Biorender.com.