An overview of the preclinical discovery and development of remdesivir for the treatment of coronavirus disease 2019 (COVID-19)

Abstract

Introduction: Remdesivir (RDV) is an inhibitor of the viral RNA-dependent RNA polymerases that are active in some RNA viruses, including the Ebola virus and zoonotic coronaviruses. When severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was identified as the etiologic agent of the coronavirus disease 2019 (COVID-19), several investigations have assessed the potential activity of RDV in inhibiting viral replication, giving rise to hope for an effective treatment.

Areas covered: In this review, the authors describe the main investigations leading to the discovery of RDV and its subsequent development as an antiviral agent, focusing on the main clinical trials investigating its efficacy in terms of symptom resolution and mortality reduction.

Expert opinion: RDV is the most widely investigated antiviral drug for the treatment of COVID-19. This attention on RDV activity against SARS-CoV-2 is justified by promising in vitro studies, which demonstrated that RDV was able to suppress viral replication without significant toxicity. Such activity was confirmed by an investigation in an animal model and by the results of preliminary clinical investigations. Nevertheless, the efficacy of RDV in reducing mortality has not been clearly demonstrated.

Keywords: COVID-19; Coronavirus; Dexamethasone; RNA polymerase; Remdesivir.

Figure 1

Lifecycle of a coronavirus as represented by the SARS-CoV-1/2 and MERS-CoV. SARS-CoV-2 enters target cells by binding with the S protein of the ACE2 receptor on the cell surface. Remdesivir specifically inhibits the activity of the viral RNA-dependent RNA-polymerase (RdRp), which is essential in viral replication. Upon entry into the cell, remdesivir is rapidly metabolized into nucleoside monophosphate (GS-441542 MP), which is then further processed into the active triphosphate form (GS-441524). GS-441524 is an adenosine triphosphate (ATP) analog and thus, it can be used as a substrate by the viral RdRp. GS-441524 outcompetes ATP for incorporation into the newly synthesised RNA strand, ultimately causing premature termination of the RNA product. The incorporation of GS-441524 causes delayed chain-termination downstream of this site

Figure 2

After entering the cell, the prodrug GS-5734 is metabolized into the nucleoside monophosphate form (GS-44154), through the synthesis of the intermediate metabolite GS-704277. GS-44154 undergoes further phosphorylation via the endogenous phosphorylation pathway, generating the analog form of the active nucleoside triphosphate GS-441524