Identification of broad-spectrum M inhibitors: a focus on high-risk coronaviruses and conserved interactions.

The COVID-19 pandemic underscores the urgent need to develop broad-spectrum antivirals against coronaviruses (CoVs) to prepare for future outbreaks. In this study, we presented a systematic approach to developing broad-spectrum M inhibitors, with a focus on high-risk CoVs. We optimised as a lead compound, with the goal of enhancing conserved interactions within the S1, S2, and S3/S4 pockets of M, leading to significantly improved inhibitory potency against representative CoVs. Compound exhibited submicromolar activity across all ten CoVs, with IC values below 0.1 μM for six of them. The X-ray co-crystal structure of SARS-CoV-2 M in complex with compound revealed the structural basis of conserved interactions contributing to its broad-spectrum activity. This study demonstrates the feasibility of reinforcing conserved interactions to develop M inhibitors with broad-spectrum activity and provides valuable strategies for combating future pandemics caused by unknown CoVs.