Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities

The newly emerged coronavirus, called SARS-CoV-2, is the causing pathogen of pandemic COVID-19. The identification of drugs to treat COVID-19 and other coronavirus diseases is an urgent global need, thus different strategies targeting either virus or host cell are still under investigation. Direct-acting agents, targeting protease and polymerase functionalities, represent a milestone in antiviral therapy. The 3C-like (or Main) protease (3CL(Pro)) and the nsp12 RNA-dependent RNA-polymerase (RdRp) are the best characterized SARS-CoV-2 targets and show the highest degree of conservation across coronaviruses fostering the identification of broad-spectrum inhibitors. Coronaviruses also possess a papain-like protease, another essential enzyme, still poorly characterized and not equally conserved, limiting the identification of broad-spectrum agents. Herein, we provide an exhaustive comparative analysis of SARS-CoV-2 proteases and RdRp with respect to other coronavirus homologues. Moreover, we highlight the most promising inhibitors of these proteins reported so far, including the possible strategies for their further development.

Automated summary

This article discusses the urgent need to identify drugs for treating COVID-19 and other coronavirus diseases. Different strategies targeting the virus or host cells are being investigated. The article provides a comprehensive comparative analysis of SARS-CoV-2 proteases and RdRp with other coronavirus counterparts, highlighting the most promising inhibitors reported so far and potential strategies for further development.