2. Academic Validation
  3. Discovery of 3-phenyl-1H-5-pyrazolylamides as PLpro inhibitors through virtual screening and structure optimization

Discovery of 3-phenyl-1H-5-pyrazolylamides as PLpro inhibitors through virtual screening and structure optimization

  • Bioorg Med Chem Lett. 2025 Nov 1:127:130293. doi: 10.1016/j.bmcl.2025.130293.
Chengwei Wu 1,  Mengdie Ou 2,  Bo Qin 3,  Shuo Wang 1,  Peng Li 1,  Sheng Cui 4,  Haihong Huang 5,  Gang Li 6
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
  • 2 Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), National Institute of Pathogen Biology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 102629, PR China.
  • 3 Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), National Institute of Pathogen Biology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 102629, PR China. Electronic address: qinbo@pumc.edu.cn.
  • 4 Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), National Institute of Pathogen Biology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 102629, PR China; State Key Laboratory of Respiratory Health and Multimorbidity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, PR China. Electronic address: cui.sheng@ipb.pumc.edu.cn.
  • 5 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; State Key Laboratory of Respiratory Health and Multimorbidity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, PR China. Electronic address: joyce@imm.ac.cn.
  • 6 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; State Key Laboratory of Respiratory Health and Multimorbidity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, PR China. Electronic address: ligang@imm.ac.cn.
PMID: 40473007 DOI: 10.1016/j.bmcl.2025.130293
Abstract

The papain-like protease (PLpro) of SARS-CoV-2 has been identified as a pivotal enzyme in viral replication, indicating it a promising target for drug discovery. Utilizing a virtual screening strategy, compound 1 with the N-(3-(5-amino-1H-pyrazol-3-yl)phenyl) benzenesulfonamide scaffold was discovered as a hit targeting PLpro. Structural modification from virtually screened hit 1 led to the development of a series of substituted 3-phenyl-1H-5-pyrazolylamide derivatives. Notably, compounds 14h and 14e exhibited improved PLpro inhibitory activity (IC50 = 14.2 μM and 12.0 μM, respectively) and low cytotoxicity. Further biological evaluation revealed that compound 14e with a thiophene aldehyde group displayed potent binding activity (KD = 1.86 μM). This 3-phenyl-1H-5-pyrazolylamide scaffold offers significant potential for further development as a novel class of PLpro inhibitors.

Keywords

3-Phenyl-1H-5-pyrazolylamide; PLpro; Structure optimization; Virtual screening.

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