A Novel Y-Shaped, S–O–N–O–S-Bridged Cross-Link between Three Residues C22, C44, and K61 Is Frequently Observed in the SARS-CoV-2 Main Protease
Kai S. Yang, Lauren R. Blankenship, Syuan‐Ting Kuo, Yan Sheng, Pingwei Li, Carol A. Fierke, David H. Russell, Xin Yan, Shiqing Xu, Wenshe Ray Liu
Abstract
As the COVID-19 pathogen, SARS-CoV-2 relies on its main protease (M Pro ) for pathogenesis and replication. During crystallographic analyses of M Pro crystals that were exposed to the air, a uniquely Y-shaped, S–O–N–O–S-bridged post-translational cross-link that connects three residues C22, C44, and K61 at their side chains was frequently observed. As a novel covalent modification, this cross-link serves potentially as a redox switch to regulate the catalytic activity of M Pro, a demonstrated drug target of COVID-19. The formation of this linkage leads to a much more open active site that can potentially be targeted for the development of novel SARS-CoV-2 antivirals. The structural rearrangement of M Pro by this cross-link indicates that small molecules that lock M Pro in the cross-linked form can potentially be used with other active-site-targeting molecules such as paxlovid for synergistic effects in inhibiting SARS-CoV-2 viral replication.