A comparative analysis of remdesivir and other repurposed antivirals against SARS-CoV-2

Abstract

The ongoing SARS-CoV-2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID-19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID-19. It is to date the only approved antiviral for treating COVID-19. Here, we provide a mechanism and evidence-based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; antivirals; remdesivir.

Figure 1. Life cycle of SARS‐CoV‐2 and antiviral drug targets

Attachment of SARS‐CoV‐2 to its host cell is mediated by binding of the viral spike protein to the ACE2 receptor. After proteolytic cleavage of the S1 domain by the membrane‐anchored serine protease TMPRSS2, fusion of the viral and host cell membrane is initiated by the exposed S2 subunit. Alternatively, SARS‐CoV‐2 can invade the host cell upon endosomal uptake and activation of the spike protein by cathepsin L. Released viral RNA is translated by ribosomes of the host cell. Polyproteins pp1a/pp1ab are cleaved mainly by the viral main protease (3C‐like proteinase). Released non‐structural proteins form the replicase–transcriptase complex, which initiates the viral RNA synthesis machinery. Viral structure proteins and genomic RNA form new particles, which are released by exocytosis. The replication cycle of SARS‐CoV‐2 can be inhibited at various stadiums: viral entry (1‐2); protease inhibition (3), and RNA replication (4).