2. Academic Validation
  3. DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

  • Commun Chem. 2023 Aug 4;6(1):164. doi: 10.1038/s42004-023-00961-y.
Ravikumar Jimmidi # 1,  Srinivas Chamakuri # 2,  Shuo Lu # 3,  Melek Nihan Ucisik 1,  Peng-Jen Chen 1,  Kurt M Bohren 1,  Seyed Arad Moghadasi 4,  Leroy Versteeg 5 6,  Christina Nnabuife 3,  Jian-Yuan Li 1,  Xuan Qin 1,  Ying-Chu Chen 1,  John C Faver 1,  Pranavanand Nyshadham 1,  Kiran L Sharma 1,  Banumathi Sankaran 7,  Allison Judge 3,  Zhifeng Yu 1,  Feng Li 1 3,  Jeroen Pollet 5 6,  Reuben S Harris 8 9,  Martin M Matzuk 1 3,  Timothy Palzkill 10,  Damian W Young 11 12
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA.
  • 2 Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA. srinivas.chamakuri@bcm.edu.
  • 3 Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA.
  • 4 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455, USA.
  • 5 Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, 77030, USA.
  • 6 Center for Vaccine Development, Texas Children's Hospital, 1102 Bates Street, Houston, Texas, 77030, USA.
  • 7 Department of Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, California, 94720, USA.
  • 8 Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, Texas, 78229, USA.
  • 9 Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, Texas, 78229, USA.
  • 10 Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA. timothyp@bcm.edu.
  • 11 Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA. damian.young@bcm.edu.
  • 12 Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA. damian.young@bcm.edu.
  • # Contributed equally.
PMID: 37542196 DOI: 10.1038/s42004-023-00961-y
Abstract

The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

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