BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease.

Numerous organic molecules are known to inhibit the main protease (M) of SARS-CoV-2, the pathogen of Coronavirus Disease 2019 (COVID-19). Guided by previous research on zinc-ligand inhibitors of M and zinc-dependent histone deacetylases (HDACs), we identified BRD4354 as a potent inhibitor of M. The protease activity assays show that BRD4354 displays time-dependent inhibition against M with an IC (concentration that inhibits activity by 50%) of 0.

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.

As the COVID-19 pathogen, SARS-CoV-2 relies on its main protease (M) for pathogenesis and replication. During crystallographic analyses of M 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, a demonstrated drug target of COVID-19.