t-1105 and Coronavirus-Infections

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.

Topics: Amides; Animals; Antiviral Agents; Betacoronavirus; Chlorocebus aethiops; Coronavirus Infections; Coronavirus RNA-Dependent RNA Polymerase; COVID-19; COVID-19 Drug Treatment; Models, Molecular; Mutagenesis; Pandemics; Pneumonia, Viral; Pyrazines; RNA-Dependent RNA Polymerase; RNA, Viral; SARS-CoV-2; Sequence Analysis; Vero Cells; Viral Nonstructural Proteins; Virus Replication