2. Academic Validation
  3. Structure-Based Design of a Dual-Targeted Covalent Inhibitor Against Papain-like and Main Proteases of SARS-CoV-2

Structure-Based Design of a Dual-Targeted Covalent Inhibitor Against Papain-like and Main Proteases of SARS-CoV-2

  • J Med Chem. 2022 Dec 22;65(24):16252-16267. doi: 10.1021/acs.jmedchem.2c00954.
Wenying Yu 1,  Yucheng Zhao 2,  Hui Ye 1 3,  Nanping Wu 4 5,  Yixian Liao 1,  Nannan Chen 1,  Zhiling Li 1,  Ning Wan 1 3,  Haiping Hao 1 3,  Honggao Yan 1 6,  Yibei Xiao 1 6,  Maode Lai 1 4 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing210009, China.
  • 2 Department of Resources Science of Traditional Chinese Medicines and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing210009, China.
  • 3 Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing210009, China.
  • 4 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou310003, China.
  • 5 First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou310003, China.
  • 6 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing310003, China.
  • 7 School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing210009, China.
PMID: 36503248 DOI: 10.1021/acs.jmedchem.2c00954
Abstract

The two proteases, PLpro and Mpro, of SARS-CoV-2 are essential for replication of the virus. Using a structure-based co-pharmacophore screening approach, we developed a novel dual-targeted inhibitor that is equally potent in inhibiting PLpro and Mpro of SARS-CoV-2. The inhibitor contains a novel warhead, which can form a covalent bond with the catalytic cysteine residue of either Enzyme. The maximum rate of the covalent inactivation is comparable to that of the most potent inhibitors reported for the viral proteases and covalent inhibitor drugs currently in clinical use. The covalent inhibition appears to be very specific for the viral proteases. The inhibitor has a potent Antiviral activity against SARS-CoV-2 and is also well tolerated by mice and rats in toxicity studies. These results suggest that the inhibitor is a promising lead for development of drugs for treatment of COVID-19.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-152101
    98.01%, SARS-CoV-2 PLpro/Mpro抑制剂
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