2. Academic Validation
  3. Nicotine-Inspired, De Novo-Designed SARS-CoV-2 Main Protease Inhibitors Reveal Unique Chemistry for Covalently Conjugating Both Cysteine and Histidine Residues in the Catalytic Dyad

Nicotine-Inspired, De Novo-Designed SARS-CoV-2 Main Protease Inhibitors Reveal Unique Chemistry for Covalently Conjugating Both Cysteine and Histidine Residues in the Catalytic Dyad

  • J Am Chem Soc. 2026 Apr 29;148(16):16985-16995. doi: 10.1021/jacs.6c01119.
Sandeep Atla 1,  Veerabhadra Vulupala 1,  Yugendar R Alugubelli 1,  Lauren R Blankenship 1,  Kai Yang 1,  Satyanarayana Nyalata 1,  Kaustav Khatua 1,  Demonta Coleman 1,  Dorsa Rabie 1,  Xuejiao Guo 1,  Chia-Chuan D Cho 1,  Sathish Kumar 2 3,  Lai Hoang Son Le 1,  Banumathi Sankaran 4,  Justin K Kalugin 5,  Shivangi Sharma 1,  Benjamin W Neuman 2,  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, Texas A&M University, College Station, Texas 77843, United States.
  • 2 Department of Biology, College of Arts and Sciences, Texas A&M University, College Station, Texas 77843, United States.
  • 3 Texas A&M Global Health Research Complex, Texas A&M University, College Station, Texas 77843, United States.
  • 4 Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Laurence Berkeley National Laboratory, Berkeley, California 94720, United States.
  • 5 Division of Chemical Biology and Medicinal Chemistry, The University of Texas, Austin, Texas 78712, United States.
  • 6 Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, College Station, Texas 77843, United States.
  • 7 Institute of Biosciences and Technology and Department of Translational Medical Sciences, College 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, College of Medicine, Texas A&M University, College Station, Texas 77843, United States.
PMID: 41978983 DOI: 10.1021/jacs.6c01119
Abstract

Anecdotal reports about smokers with low SARS-CoV-2 Infection rates prompted a search for nicotine and its pyrolysis products as SARS-CoV-2 main protease (MPro) inhibitors. From this search, 3-vinylpyridine was discovered as a weak binder for the MPro S1 subsite and was used subsequently as a de novo starting point for covalent inhibitor design that quickly yielded a highly potent inhibitor, SR-A-174, with an IC50 value of 60 nM. Representing a novel class of MPro inhibitors, SR-A-174 features an N,N-diaryl-α,α-dichloroacetamide scaffold that facilitated rapid exploration of alternative covalent warheads and various N-substituents, leading to the identification of multiple inhibitors with potent Antiviral activity. Eight such MPro inhibitor structures were determined, all demonstrating covalent binding to catalytic Cys145 of MPro. In six determined structures, binding is dominated by the covalent bond plus van der Waals contacts, which contrasts with the extensive hydrogen bond networks formed with peptidomimetic inhibitors such as nirmatrelvir. Strikingly, two N,N-diaryl-α,α-dichloroacetamide inhibitors exhibit an unprecedented dual covalent modification mode of the catalytic dyad, forming bonds to both Cys145 and His41 with a concomitant loss of both chlorides and displacing the inhibitors from the S1 subsite. This dyad-targeting reactivity suggests a novel route for bioconjugation of both cysteine and histidine.

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