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
  • 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: [email protected].
  • 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: [email protected].
  • 7. Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China. Electronic address: [email protected].
  • 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: [email protected].
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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