Yan J. Sheng
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Research Subjects
Yan J. Sheng has a total of 8 co-authors. Here are the top co-authors by number of shared publications:
- Carol A. Fierke
Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United States
1 shared publication - David H. Russell
Texas A&M University
1 shared publication Hanyuan E. Zhang
Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
1 shared publication- Shiqing Xu
Texas A&M University
1 shared publication Syuan-Ting A. Kuo
Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
1 shared publicationTingyuan Yang
Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
1 shared publication
Latest Publications
- 8 February 2024
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 63 (4) , 402-406
BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease
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 μM 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 μM 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.
- 8 February 2024
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 63 (4) , 402-406
BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease
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 μM 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 μM 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.