DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors PMID: 37542196

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
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. [email protected].
11. Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA. [email protected].
12. Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA. [email protected].
# Contributed equally.

Abstract

The development of SARS-CoV-2 main protease (M^pro) 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 M^pro 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 M^pro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M^pro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M^pro with low nanomolar K_i values. Furthermore, these compounds demonstrate efficacy against mutant forms of M^pro 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.