SARS-CoV-2 main protease (M-pro) mutational profiling: An insight into mutation coldspots
Pol Garcia‐Segura, Ariadna Llop‐Peiró, Nil Novau-Ferré, Júlia Mestres‐Truyol, Bryan Saldivar‐Espinoza, Gerard Pujadas, Santiago Garcı́a-Vallvé
Abstract
SARS-CoV-2 and the COVID-19 pandemic have marked a milestone in the history of scientific research worldwide. To ensure that treatments are successful in the mid-long term, it is crucial to characterize SARS-CoV-2 mutations, as they might lead to viral resistance. Data from >5,700,000 SARS-CoV-2 genomes available at GISAID was used to report SARS-CoV-2 mutations. Given the pivotal role of its main protease (M-pro) in virus replication, a detailed analysis of SARS-CoV-2 M-pro mutations was conducted, with particular attention to mutation-resistant residues or mutation coldspots, defined as those residues that have mutated in five or fewer genomes. 32 mutation coldspots were identified, most of which mediate interprotomer interactions or funneling interaction networks from the substrate-binding site towards the dimerization surface and vice versa . Besides, mutation coldspots were virtually conserved in all main proteases from other CoVs. Our results provide valuable information about key residues to M-pro structure that could be useful in rational target-directed drug design and establish a solid groundwork based on mutation analyses for the inhibition of M-pro dimerization, with a potential applicability to future coronavirus outbreaks. • Coldspots (residues with fewer mutations) are key for M-pro structure and function. • From >5.7M genomes, we have identified 32 mutation coldspots in SARS-CoV-2 M-pro. • Most M-pro mutation coldspots mediate vital interprotomer interactions. • Most coldspots are conserved in various coronaviruses, underlining their importance. • Our findings establish a robust foundation for inhibiting M-pro dimerization.