2. Academic Validation
  3. Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening

Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening

  • Nat Commun. 2025 Jan 2;16(1):152. doi: 10.1038/s41467-024-55421-5.
Hengrui Liu 1,  Arie Zask 2,  Farhad Forouhar 3,  Sho Iketani 4 5,  Alana Williams 1,  Daniel R Vaz 1,  Dahlya Habashi 2,  Karenna Choi 2,  Samuel J Resnick 6,  Seo Jung Hong 7,  David H Lovett 4 5,  Tian Bai 4 5,  Alejandro Chavez 8,  David D Ho 4 5 9,  Brent R Stockwell 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Chemistry, Columbia University, New York, NY, USA.
  • 2 Department of Biological Sciences, Columbia University, New York, NY, USA.
  • 3 Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
  • 4 Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY, USA.
  • 5 Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 6 Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 7 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 8 Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
  • 9 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • 10 Department of Chemistry, Columbia University, New York, NY, USA. bstockwell@columbia.edu.
  • 11 Department of Biological Sciences, Columbia University, New York, NY, USA. bstockwell@columbia.edu.
  • 12 Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. bstockwell@columbia.edu.
  • 13 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. bstockwell@columbia.edu.
PMID: 39747827 DOI: 10.1038/s41467-024-55421-5
Abstract

Variants of SARS-CoV-2 have continued to emerge across the world and cause hundreds of deaths each week. Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies, additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Here, we screen 2.8 billion compounds from a DNA-encoded chemical library and identify small molecules that are non-covalent inhibitors targeting the conserved 3CL protease of SARS-CoV-2 and Other coronaviruses. We perform structure-based optimization, leading to the creation of a series of potent, non-covalent SARS-CoV-2 3CL Protease Inhibitors, for coronavirus infections. To characterize their binding mechanism to the 3CL protease, we determine 16 co-crystal structures and find that optimized inhibitors specifically interact with both protomers of the native homodimer of 3CL protease. Since 3CL protease is catalytically competent only in the dimeric state, these data provide insight into the design of drug-like inhibitors targeting the native homodimer state. With a binding mode different from the covalent 3CL inhibitor nirmatrelvir, the protease inhibitor in the COVID drug Paxlovid, these compounds may overcome resistance reported for nirmatrelvir and complement its clinical utility.

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