The complexity of targeting coronavirus nsp15 endoribonuclease for antiviral drug design

Abstract:In the past two decades, three highly pathogenic zoonotic coronaviruses (CoVs) have suddenly entered the human population: SARS-CoV, MERS-CoV and SARS-CoV-2 (the cause of COVID-19). The total lack of medication explains the tremendous impact of the COVID-19 pandemic. Besides, four low pathogenic human CoVs are continuously circulating and responsible for respiratory illness with mild to severe outcome. CoVs also cause serious economic losses in the livestock industry. The high burden of existing CoVs and likelihood that CoV outbreaks will further occur in the future, implicate an urgent need for antiviral drugs with pancoronavirus activity. In this project, we focus on drug development against CoV nsp15, an essential, multifunctional and only partially understood viral protein. Nsp15 is associated with the viral replication-transcription machinery and, via its endonuclease activity, viral evasion from innate immunity, however its precise role in these processes is not known. The fact that nsp15 is highly conserved among human and animal CoVs makes it an ideal pan-coronavirus drug target. Starting from our recent discovery of two first-in-class CoV nsp15 inhibitors, we will perform in-depth biochemical and cellbased investigations to unravel the antiviral mechanism of action and yield new insights in the enigmatic CoV nsp15 protein. In addition, structure-guided lead optimization will deliver a class of nsp15 inhibitors with high relevance for further development.

Publication year:2025

Accessibility:Embargoed