2. Academic Validation
  3. SARS-CoV-2 Main Protease Inhibitors That Leverage Unique Interactions with the Solvent Exposed S3 Site of the Enzyme

SARS-CoV-2 Main Protease Inhibitors That Leverage Unique Interactions with the Solvent Exposed S3 Site of the Enzyme

  • ACS Med Chem Lett. 2024 May 20;15(6):950-957. doi: 10.1021/acsmedchemlett.4c00146.
Lauren R Blankenship 1,  Kai S Yang 1,  Veerabhadra R Vulupala 1,  Yugendar R Alugubelli 1,  Kaustav Khatua 1,  Demonta Coleman 1,  Xinyu R Ma 1,  Banumathi Sankaran 2,  Chia-Chuan D Cho 1,  Yuying Ma 1,  Benjamin W Neuman 3 4 5,  Shiqing Xu 1 6,  Wenshe Ray Liu 1 6 7 8 9
Affiliations

Affiliations

  • 1 Texas A&M Drug Discovery Center and Department of Chemistry, College of Arts and Scienes, Texas A&M University, College Station, Texas 77843, United States.
  • 2 Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Laurence Berkeley National National Laboratory, Berkeley, California 94720, United States.
  • 3 Department of Biology, College of Arts and Sciences, Texas A&M University, College Station, Texas 77843, United States.
  • 4 Texas A&M Global Health Research Complex, Texas A&M University, College Station, Texas 77843, United States.
  • 5 Department of Molecular Pathogenesis and Immunology, School of Medicine, Texas A&M University, College Station, Texas 77843, United States.
  • 6 Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, College Station, Texas 77843, United States.
  • 7 Institute of Biosciences and Technology and Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, Texas 77030, United States.
  • 8 Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas 77843, United States.
  • 9 Department of Cell Biology and Genetics, School of Medicine, Texas A&M University, College Station, Texas 77843, United States.
PMID: 38894905 DOI: 10.1021/acsmedchemlett.4c00146
Abstract

The main protease (MPro) of SARS-CoV-2 is crucial for the virus's replication and pathogenicity. Its active site is characterized by four distinct pockets (S1, S2, S4, and S1-3') and a solvent-exposed S3 site for accommodating a protein substrate. During X-ray crystallographic analyses of MPro bound with dipeptide inhibitors containing a flexible N-terminal group, we often observed an unexpected binding mode. Contrary to the anticipated engagement with the deeper S4 pocket, the N-terminal group frequently assumed a twisted conformation, positioning it for interactions with the S3 site and the inhibitor component bound at the S1 pocket. Capitalizing on this observation, we engineered novel inhibitors to engage both S3 and S4 sites or to adopt a rigid conformation for selective S3 site binding. Several new inhibitors demonstrated high efficacy in MPro inhibition. Our findings underscore the importance of the S3 site's unique interactions in the design of future MPro inhibitors as potential COVID-19 therapeutics.

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