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
-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.
Authors
- Sandeep Atla (ORCID: https://orcid.org/0000-0001-9960-5429)
- Yugendar R. Alugubelli
- Lauren R. Blankenship (ORCID: https://orcid.org/0000-0002-1714-4399)
- Banumathi Sankaran (ORCID: https://orcid.org/0000-0002-3266-8131)
- Dorsa Rabie
- Benjamin W. Neuman (ORCID: https://orcid.org/0000-0003-1240-8954)
- Wenshe Ray Liu (ORCID: https://orcid.org/0000-0002-7078-6534)
- Kaustav Khatua (ORCID: https://orcid.org/0000-0002-2497-3187)
- Shiqing Xu (ORCID: https://orcid.org/0000-0001-6260-9290)
- Shivangi Sharma
- Justin K. Kalugin
- Kai Yang
- Satyanarayana Nyalata (ORCID: https://orcid.org/0009-0009-6717-5941)
- Veerabhadra Vulupala
- Demonta Coleman
- Xuejiao Guo
- Chia-Chuan D. Cho
- Sathish Kumar
- Lai Hoang Son Le (ORCID: https://orcid.org/0000-0002-2473-6309)
Institutions
- Lawrence Berkeley National Laboratory (US)
- Institute of Rural Management Anand (IN)
- Mitchell Institute (US)
- Texas A&M Health Science Center (US)
- Drug Discovery Laboratory (Norway) (NO)
- Pediatrics and Genetics (US)
- Institute of Medicinal Plant Development (CN)
- Institute of Molecular Biology and Biophysics (RU)
- The University of Texas at Austin (US)
- Texas A&M University (US)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2026-04-14
- DOI
- https://doi.org/10.1021/jacs.6c01119
- Primary Topic
- Click Chemistry and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Energy
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- Texas A and M University
- National Institutes of Health
- Office of Science
- National Institute of General Medical Sciences