Academic Journal
BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV‑2 Main Protease
| العنوان: | BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV‑2 Main Protease |
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| المؤلفون: | Yan J. Sheng, Syuan-Ting A. Kuo, Tingyuan Yang, Hanyuan E. Zhang, David H. Russell, Xin Yan, Shiqing Xu, Wenshe R. Liu, Carol A. Fierke |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | Biophysics, Biochemistry, Cell Biology, Molecular Biology, Pharmacology, Immunology, Infectious Diseases, Chemical Sciences not elsewhere classified, coronavirus disease 2019, addition reaction mechanism, dependent histone deacetylases, 9 ± 0, 72 ± 0, 5 μm followed, 040 ± 0, catalytic cysteine c145, brd4354 displays time, max , pro , potent covalent inhibitor, 50 , potent inhibitor, , dependent inhibition, 50 %), 04 μm, vitro <, ortho <, k <, covalent intermediate |
| الوصف: | Numerous organic molecules are known to inhibit the main protease (M Pro ) of SARS-CoV-2, the pathogen of Coronavirus Disease 2019 (COVID-19). Guided by previous research on zinc-ligand inhibitors of M Pro and zinc-dependent histone deacetylases (HDACs), we identified BRD4354 as a potent inhibitor of M Pro . The in vitro protease activity assays show that BRD4354 displays time-dependent inhibition against M Pro with an IC 50 (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 K I of 1.9 ± 0.5 μM followed by a second slow inactivation step, k inact,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 M Pro . Based on these data, a Michael-addition reaction mechanism between M Pro 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://figshare.com/articles/journal_contribution/BRD4354_Is_a_Potent_Covalent_Inhibitor_against_the_SARS-CoV_2_Main_Protease/25188336 |
| DOI: | 10.1021/acs.biochem.3c00685.s001 |
| الاتاحة: | https://doi.org/10.1021/acs.biochem.3c00685.s001 https://figshare.com/articles/journal_contribution/BRD4354_Is_a_Potent_Covalent_Inhibitor_against_the_SARS-CoV_2_Main_Protease/25188336 |
| Rights: | CC BY-NC 4.0 |
| رقم الانضمام: | edsbas.246D7664 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.biochem.3c00685.s001 |
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