Dynamic Combinatorial Chemistry Unveils Nsp10 Inhibitors with Antiviral Potential Against SARS‐CoV‐2

Abstract

The development of antiviral drugs against the Severe Acute Respiratory Syndrome coronavirus 2 (SARS‐CoV‐2) responsible for the recent Covid‐19 pandemic is crucial, as treatment options remain limited and vaccination does not prevent (re)infection. Two relatively underexplored targets of this virus are the 3′‐5′ exoribonuclease (ExoN) and the 2’‐O‐methyltransferase (2′‐O‐Mtase), both essential for the viral viability. The non‐structural protein Nsp14 and Nsp16 exhibit enzymatic activities for ExoN and 2′‐O‐Mtase, respectively, especially when in complex with their co‐factor protein Nsp10. The study focuses on the use of target‐directed dynamic combinatorial chemistry (tdDCC) to identify binders of Nsp10, aiming to disturb the protein‐protein interactions (PPI) involving Nsp10–Nsp14, as well as Nsp10–Nsp16. We synthesised the hits and evaluated them to assess Nsp10 affinity, ExoN and 2′‐O‐Mtase activities inhibition, and anti‐viral activity in hCoV‐229E and SARS‐CoV‐2 infected whole‐cell setting. This study reports a novel class of ExoN and/or 2′‐O‐Mtase inhibitors exhibiting anti‐viral activity against coronaviruses.