2. Academic Validation
  3. Identification of broad-spectrum Mpro inhibitors: a focus on high-risk coronaviruses and conserved interactions

Identification of broad-spectrum Mpro inhibitors: a focus on high-risk coronaviruses and conserved interactions

  • J Enzyme Inhib Med Chem. 2025 Dec;40(1):2503961. doi: 10.1080/14756366.2025.2503961.
Man Liu 1 2,  Li Zhao 2 3,  Xupeng Huang 2,  Zhenhao Tang 2,  Yihang Zhong 2,  Mengrong Yan 2,  Shun Liu 2 4,  Shunjing Wang 2 4,  Zeyun Sun 2 3,  Zixuan Rao 2 4,  Linyi Yu 2 4,  Yuying Fang 1 2,  Wei Zhang 1 2 4,  Hongbo Zhang 5,  Wei Peng 1 2 3 4 6
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China.
  • 2 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou, China, China.
  • 3 Guangzhou Medical University, Guangzhou, China.
  • 4 University of South China, Hengyang, China.
  • 5 Beijing StoneWise Technology Co. Ltd, Beijing, China.
  • 6 Lead contact.
PMID: 40396609 DOI: 10.1080/14756366.2025.2503961
Abstract

The COVID-19 pandemic underscores the urgent need to develop broad-spectrum antivirals against coronaviruses (CoVs) to prepare for future outbreaks. In this study, we presented a systematic approach to developing broad-spectrum Mpro inhibitors, with a focus on high-risk CoVs. We optimised S-217622 as a lead compound, with the goal of enhancing conserved interactions within the S1, S2, and S3/S4 pockets of Mpro, leading to significantly improved inhibitory potency against representative CoVs. Compound 25 exhibited submicromolar activity across all ten CoVs, with IC50 values below 0.1 μM for six of them. The X-ray co-crystal structure of SARS-CoV-2 Mpro in complex with compound 25 revealed the structural basis of conserved interactions contributing to its broad-spectrum activity. This study demonstrates the feasibility of reinforcing conserved interactions to develop Mpro inhibitors with broad-spectrum activity and provides valuable strategies for combating future pandemics caused by unknown CoVs.

Keywords

Broad-spectrum; Mpro inhibitors; conserved interactions.

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