2. Academic Validation
  3. Development of pyrimidone derivatives as nonpeptidic and noncovalent 3-chymotrypsin-like protease (3CLpro) inhibitors with anti-coronavirus activities

Development of pyrimidone derivatives as nonpeptidic and noncovalent 3-chymotrypsin-like protease (3CLpro) inhibitors with anti-coronavirus activities

  • Bioorg Chem. 2024 Nov 22:154:107988. doi: 10.1016/j.bioorg.2024.107988.
Fan Pan 1,  Qifan Zhou 2,  Ming Yan 3,  Sidi Yang 4,  Ruiyu Hu 1,  Yongzhi Chen 1,  Yuanmei Wen 1,  Yang Chao 1,  Cailing Xie 4,  Weixin Ou 4,  Yingjun Li 5,  Hongmin Zhang 6,  Deyin Guo 7,  Xumu Zhang 8
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China.
  • 2 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China. Electronic address: zhouqf@sustech.edu.cn.
  • 3 Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518000, China.
  • 4 Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China.
  • 5 State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510180, China.
  • 6 Institute of High Energy Physics, CAS, Beijing 100000, China; China Spallation Neutron Source, CAS, Dongguan, Guangdong 523000, China. Electronic address: zhanghongmin@ihep.ac.cn.
  • 7 Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China. Electronic address: guo_deyin@gzlab.ac.cn.
  • 8 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China. Electronic address: zhangxm@sustech.edu.cn.
PMID: 39591689 DOI: 10.1016/j.bioorg.2024.107988
Abstract

3CLPro is crucial to the life cycle of SARS-CoV-2 and exhibits high sequence similarity with Other coronaviruses, while being absent in human proteases. This makes it an ideal target for developing broad-spectrum Antiviral drugs. Ensitrelvir (S-217622) is the only launched non-covalent, non-peptidomimetic 3CLPro inhibitor, offering certain advantages in terms of dosage and metabolism. Using S-217622 as the lead, we designed and synthesized 43 pyrimidone derivatives and conducted a systematic evaluation of their structure-activity relationships. Among them, A36 exhibited strong inhibitory activity against several β-coronaviruses and demonstrated low cytotoxicity. A36 also displayed moderate stability in mouse liver microsomes. Co-crystal structure analysis of 3CLPro in complex with A36 revealed the similar binding mode with S-217622. A36 shows strong potential as a promising lead for broad-spectrum anti-coronavirus therapy, warranting further investigation.

Keywords

3CL(Pro); Anti-coronavirus; Pyrimidone derivatives; S-217622.

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