BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease. Academic Article uri icon

abstract

  • Numerous organic molecules are known to inhibit the main protease (MPro) of SARS-CoV-2, the pathogen of Coronavirus Disease 2019 (COVID-19). Guided by previous research on zinc-ligand inhibitors of MPro and zinc-dependent histone deacetylases (HDACs), we identified BRD4354 as a potent inhibitor of MPro. The in vitro protease activity assays show that BRD4354 displays time-dependent inhibition against MPro with an IC50 (concentration that inhibits activity by 50%) of 0.72 0.04 M after 60 min of incubation. Inactivation follows a two-step process with an initial rapid binding step with a KI of 1.9 0.5 M followed by a second slow inactivation step, kinact,max of 0.040 0.002 min-1. Native mass spectrometry studies indicate that a covalent intermediate is formed where the ortho-quinone methide fragment of BRD4354 forms a covalent bond with the catalytic cysteine C145 of MPro. Based on these data, a Michael-addition reaction mechanism between MPro C145 and BRD4354 was proposed. These results suggest that both preclinical testing of BRD4354 and structure-activity relationship studies based on BRD4354 are warranted to develop more effective anti-COVID therapeutics.

published proceedings

  • Biochemistry

author list (cited authors)

  • Sheng, Y. J., Kuo, S., Yang, T., Zhang, H. E., Russell, D. H., Yan, X., ... Fierke, C. A.

citation count

  • 0

complete list of authors

  • Sheng, Yan J||Kuo, Syuan-Ting A||Yang, Tingyuan||Zhang, Hanyuan E||Russell, David H||Yan, Xin||Xu, Shiqing||Liu, Wenshe R||Fierke, Carol A

publication date

  • February 2024