Dual targeting of nsp12 and nsp15: a powerful concept to suppress coronavirus replication and transcription

To treat SARS-CoV-2 infected persons at risk of severe COVID-19 and prepare against future coronavirus (CoV) outbreaks, effective antiviral drugs are highly needed. These drugs should have broad CoV coverage and a high barrier for resistance. We here develop dual targeting of two conserved components of the viral replication-transcription complex (RTC): non-structural protein 12 (nsp12) and nsp15. Starting from lead compounds identified prior to this work, we will optimize the pan-CoV activity and disclose the inhibitory mechanism towards the virus and target protein, i.e. nsp12 polymerase or nsp15 endoribonuclease. This includes the potential of nsp15 inhibitors to boost the interferon response in infected cells. The synergy of nsp12-nsp15 inhibitor combinations will be examined. Also, the crystallographic and cryo-EM structures of the RTC core and native RTCs will be resolved to enhance anti-CoV drug development and contribute to a better structural understanding of the machinery performing CoV RNA synthesis.

Keywords:Coronavirus, Antiviral therapy, Nsp12 polymerase, Nucleoside analogue, Nsp15 endoribonuclease, Interferon, Cryo-EM structure, Replication-transcription complex

Disciplines:Virology, Non-clinical studies, Medicinal chemistry