2. Academic Validation
  3. Identification and Exploration of a Series of SARS-Cov‑2 MPro Cyano-Based Inhibitors Revealing Ortho-Substitution Effects within the P3 Biphenyl Group

Identification and Exploration of a Series of SARS-Cov‑2 MPro Cyano-Based Inhibitors Revealing Ortho-Substitution Effects within the P3 Biphenyl Group

  • ACS Med Chem Lett. 2025 Sep 25;16(10):1935-1945. doi: 10.1021/acsmedchemlett.5c00301.
Emma Clyde-Allen 1,  Mikołaj Zmudzinski 2,  Mohammad Afsar 3,  Ciyana James 1,  Anindita Nayak 3,  Digant Nayak 3,  Priscila Dos Santos Bury 3,  Dirk Jochmans 4,  Johann Neyts 4,  Christopher J Scott 5,  Shaun K Olsen 3,  Marcin Drag 2,  Rich Williams 1
Affiliations

Affiliations

  • 1 Protease Drug Development Lab, Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, Northern Ireland.
  • 2 Department of Chemical Biology and Bioimaging, Wrocław University of Science and Technology, 50-370 Wroclaw, Poland.
  • 3 Department of Biochemistry & Structural Biology and Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • 4 Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
  • 5 Future Medicines Institute, Queen's University Belfast, Belfast BT9 7AE, Northern Ireland.
PMID: 41089474 DOI: 10.1021/acsmedchemlett.5c00301
Abstract

Starting from a simple scaffold hopping exercise based on our previous exploration of cysteine Protease Inhibitors against Legumain, compound 6a was identified as a starting point for the development of a SARS-CoV-2 main protease (MPro) inhibitor. Compound 6a displayed submicromolar biochemical potency in the ultrasensitive assay developed by Drag and co-workers. Through an iterative structure-activity relationship campaign, we discovered an unexpected improvement in both biochemical and cellular potency through the incorporation of an ortho substituent within the P3 benzamide. X-ray crystallography revealed that incorporation of the ortho substituent caused a subtle but important binding enhancement of the P1 glutamate group within the MPro S1 pocket. While incorporation of the ortho substituent improved the potency, the off-target selectivity against a panel of cysteine proteases and cell activity remained suboptimal. Further scanning of the P2 core revealed that incorporation of the 3.1.0 proline could address these issues and afford compound 22e, a highly potent and cellularly active MPro inhibitor.

Keywords

COVID-19 infection; MPro inhibition; Protease inhibitor; Reversible small molecule design; Viral protease; Viral replication.

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