2. Academic Validation
  3. Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro)

Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro)

  • Eur J Med Chem. 2023 Sep 5:257:115487. doi: 10.1016/j.ejmech.2023.115487.
Kuojun Zhang 1,  Tianyu Wang 1,  Maotian Li 2,  Mu Liu 3,  He Tang 1,  Lin Wang 1,  Ke Ye 1,  Jiamei Yang 1,  Sheng Jiang 1,  Yibei Xiao 1,  Youhua Xie 4,  Meiling Lu 5,  Xiangyu Zhang 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Department of Pharmacology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Diseases and Biosecurity, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.
  • 4 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Diseases and Biosecurity, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China. Electronic address: yhxie@fudan.edu.cn.
  • 5 Department of Pharmacology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: lumeiling@cpu.edu.cn.
  • 6 Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xiangyu.zhang@cpu.edu.cn.
PMID: 37257212 DOI: 10.1016/j.ejmech.2023.115487
Abstract

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (Mpro) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 Mpro relative to baicalein (IC50 = 0.085 ± 0.006 and 0.966 ± 0.065 μM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC50 = 1.10 ± 0.12 and 5.15 ± 1.64 μM, respectively) with low cytotoxicity (CC50 ＞ 50 μM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs.

Keywords

Antiviral activity; Antiviral drugs; Noncovalent M(pro) inhibitors; SARS-CoV-2 M(pro).

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