SARS-CoV-2 main protease (M-pro) mutational profiling: An insight into mutation coldspots.

Area of Science:

• Virology
• Structural Biology
• Drug Discovery

Background:

• The COVID-19 pandemic, caused by SARS-CoV-2, necessitates understanding viral mutations for effective treatments.
• Viral mutations can lead to drug resistance, impacting the long-term success of antiviral therapies.
• The SARS-CoV-2 main protease (M-pro) is essential for viral replication and a key target for drug development.

Purpose of the Study:

• To analyze mutations in the SARS-CoV-2 main protease (M-pro).
• To identify mutation-resistant residues (coldspots) within M-pro.
• To provide insights for rational drug design targeting M-pro and potential future coronavirus outbreaks.

Main Methods:

• Analysis of over 5.7 million SARS-CoV-2 genomes from GISAID.
• Identification of M-pro mutation coldspots (mutated in ≤5 genomes).
• Structural analysis of identified coldspots and their conservation across coronaviruses.

Main Results:

• 32 M-pro mutation coldspots were identified.
• These coldspots are crucial for interprotomer interactions and substrate-binding site networks.
• Mutation coldspots are highly conserved across main proteases of other coronaviruses.

Conclusions:

• Identified M-pro coldspots offer valuable targets for structure-based drug design.
• These findings provide a foundation for developing M-pro inhibitors to combat SARS-CoV-2.
• The research has potential applications for inhibiting M-pro dimerization and addressing future coronavirus threats.