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Peer-reviewedCC BY-NC-NDACS bio & med chem Au

Structure-Based Design of New Nonpeptidic Covalent Mpro Inhibitors against SARS-CoV‑2 and Omicron Variants.

  • Honglei Bao1
  • Lingchen Sun2
  • Shilin Gong1
  • Li Qin3
  • Jiawei Xu2
  • Jianlin Wu1
  • Chunhua Ma1,2
  • Qinhai Ma4
  • Xiaojun Yao3
  • Bin Yu5
5 affiliations
  1. 1Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China.
  2. 2State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, School of Pharmaceutical Sciences, Henan Normal University, Xinxiang 453007, China.
  3. 3Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China.
  4. 4State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510000, China.
  5. 5College of Chemistry, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Zhengzhou University, Zhengzhou 450001, China.
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Abstract

The main protease (Mpro) is a prime target for anti-SARS-CoV-2 drugs. Herein, we describe the structure-based covalent modifications that generate new nonpeptidic covalent Mpro inhibitors. The compounds exhibit strong inhibition against Mpro at submicromolar levels. The deuterated lead compound exhibits submicromolar antiviral activity against wild-type SARS-CoV-2 and Omicron variants. Biolayer interferometry analysis indicates a strong binding affinity for Mpro. The mass spectrometry results confirm the covalent bonding of the compound with the cysteine residue of Mpro. Taken together, the data may support the deuterated compound as a new lead for developing anti-SARS-CoV-2 drugs and further reveal the feasibility of using chloroacetyl for structure-based covalent drug design.

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Cite

BibTeXRIS
BibTeX
@article{bao2026structurebased,
  title = {{Structure-Based Design of New Nonpeptidic Covalent Mpro Inhibitors against SARS-CoV‑2 and Omicron Variants.}},
  author = {Honglei Bao and Lingchen Sun and Shilin Gong and Li Qin and Jiawei Xu and Jianlin Wu and Chunhua Ma and Qinhai Ma and Xiaojun Yao and Bin Yu},
  journal = {ACS bio \& med chem Au},
  year = {2026},
  month = jul,
  doi = {10.1021/acsbiomedchemau.6c00072},
  url = {https://europepmc.org/article/MED/42921030},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Structure-Based Design of New Nonpeptidic Covalent Mpro Inhibitors against SARS-CoV‑2 and Omicron Variants.
AU  - Honglei Bao
AU  - Lingchen Sun
AU  - Shilin Gong
AU  - Li Qin
AU  - Jiawei Xu
AU  - Jianlin Wu
AU  - Chunhua Ma
AU  - Qinhai Ma
AU  - Xiaojun Yao
AU  - Bin Yu
PY  - 2026
DA  - 2026/07/27
JO  - ACS bio & med chem Au
DO  - 10.1021/acsbiomedchemau.6c00072
UR  - https://europepmc.org/article/MED/42921030
AB  - The main protease (Mpro) is a prime target for anti-SARS-CoV-2 drugs. Herein, we describe the structure-based covalent modifications that generate new nonpeptidic covalent Mpro inhibitors. The compounds exhibit strong inhibition against Mpro at submicromolar levels. The deuterated lead compound exhibits submicromolar antiviral activity against wild-type SARS-CoV-2 and Omicron variants. Biolayer interferometry analysis indicates a strong binding affinity for Mpro. The mass spectrometry results confirm the covalent bonding of the compound with the cysteine residue of Mpro. Taken together, the data may support the deuterated compound as a new lead for developing anti-SARS-CoV-2 drugs and further reveal the feasibility of using chloroacetyl for structure-based covalent drug design.
SN  - 2694-2437
ER  -