Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

Abstract

Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i؉3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2-Cmethylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral.

Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

“…Remdesivir, a polymerase inhibitor developed as a treatment for Ebola virus 22 is showing very promising early results and will likely be confirmed in clinical trials 23 . Another drug designed to inhibit RNA dependent RNA polymerase, including in coronaviruses, is EIDD 2801 (a N4hydroxycytidine triphosphate that is incorporated into viral RNA to promote errors in progeny RNA).…”

Simeprevir potently suppresses SARS-CoV-2 replication and synergizes with remdesivir

“…Several antivirals under study are hypothesized or proven to target the key mediator of a specific step in the SARS-CoV-2 viral replication cycle. For instance, lopinavir/ritonavir (LPV/r) and danoprevir have been proposed to inhibit the SARS-CoV-2 main protease (M pro , also called 3CL Pro ) needed for the maturation of multiple viral proteins; chloroquine (CQ) / hydroxychloroquine (HCQ) [alone or combined with azithromycin (AZ)] may abrogate viral replication by inhibiting endosomal acidification crucial for viral entry (7,8); nucleoside analogues such as remdesivir, ribavirin, favipiravir and EIDD-2801 likely inhibit the SARS-CoV-2 nsp12 RNA-dependent RNA polymerase (RdRP) and/or induce lethal mutations during viral RNA replication (9)(10)(11). Unfortunately, on the clinical aspect, LPV/r failed to demonstrate clinical benefits in well-powered randomized controlled trials (RCTs), while HCQ and/or AZ also failed to demonstrate benefits in observational studies (12)(13)(14).…”

Remdesivir in treatment of COVID-19: A systematic benefit-risk assessment

“…Currently, there is a need to identify effective, safe treatments for COVID-19 as quickly as possible, due to the ongoing pandemic. One such proposed treatment is remdesivir, which is an investigational antiviral medicine with proven activity against RNA viruses [6,7].…”