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Clinical development of antivirals against SARS-CoV-2 and its variants

Abstract

The unceasing global spread of severe acute respiratory syndrome #coronavirus 2 (#SARSCoV2) calls for the development of novel therapeutics. Although many newly developed antivirals and repurposed antivirals have been applied to the treatment of coronavirus disease 2019 (#COVID19), antivirals showing satisfactory clinical efficacy are few in number. In addition, the loss of sensitivity to variants of concern (VOCs) and lack of oral bioavailability have also limited the clinical application of some antivirals. These facts remind us to develop more potent and broad-spectrum antivirals with better pharmacokinetic/pharmacodynamic properties to fight against infections from SARS-CoV-2, its variants, and other human coronaviruses (HCoVs). In this review, we summarize the latest advancements in the clinical development of antivirals against infections by SARS-CoV-2 and its variants. 


1. Introduction

SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which has resulted in more than 771 million infection cases and 6.9 million deaths worldwide (https://covid19.who.int). The continuous emergence of SARS-CoV-2 variants of concern (VOCs) with increased infectivity and transmissibility, as well as resistance to antibody neutralization from vaccine-elicited sera and convalescent plasma, has become a major obstacle against ending the COVID-19 epidemic (Wang et al., 2021bTao et al., 2021Su et al., 2022). COVID-19 vaccination is expected to be an important strategy to prevent SARS-CoV-2 infection (Su et al., 2022). However, although many vaccines have been developed with clinical efficacy reaching 80–90 % (Golob et al., 2021), breakthrough infections caused by newly emerging SARS-CoV-2 VOCs still occur in vaccinated individuals (Townsend et al., 2021Hacisuleyman et al., 2021).

As for the development of SARS-CoV-2 antivirals, although several antivirals with SARS-CoV-2 inhibitory activity once have been approved, or recommended, for clinical use to treat COVID-19, only a few have shown significant clinical efficacy (WHOST Consortium et al., 2021), thus calling for the development of more effective and broad-spectrum antivirals to treat COVID-19 caused by SARS-CoV-2 and its variants (Lu et al., 2021Cao et al., 2021). Currently, many antivirals that are less effective or may cause serious side effects are no longer recommended for the treatment of COVID-19. Meanwhile, antivirals with greater clinical efficacy, such as Paxlovid (nirmatrelvir-ritonavir), remdesivir, and molnupiravir, are still recommended by the World Health Organization (WHO) (Lamontagne et al., 2020). In this review, we summarize the antivirals in clinical trials and clinical use according to their targets. In addition, we also discuss some promising antivirals currently in preclinical studies.

2. Targets for developing antivirals

Firstly, we discuss viral targets that play key roles in the viral replication cycle. Entry is the first step of the SARS-CoV-2 life cycle, including the following important processes: Spike (S) protein activation, receptor binding, and membrane fusion (Jackson et al., 2022). Several key viral/host factors are involved in these processes, making them important targets for the development of antivirals to inhibit viral entry. Proteolytic activation of S protein is mediated by host proteases, e.g., proprotein convertases, transmembrane serine proteases, and endosomal cysteine proteases, which can be disrupted by antivirals targeting these host proteases (Jackson et al., 2022). The receptor binding process is mediated by the interaction between the S protein and the angiotensin-converting enzyme 2 (ACE2) receptor, which can be blocked by antivirals targeting receptor-binding domain (RBD)/ACE2. The membrane fusion process is mainly mediated by important domains in the S2 subunit, which can be blocked by antivirals targeting the S2 subunit (Xia et al., 2020aJackson et al., 2022Lan et al., 2022) (Fig. 1).


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