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

Ravikumar Jimmidi; Srinivas Chamakuri; Shuo Lu; Melek Nihan Ucisik; Peng-Jen Chen; Kurt M Bohren; Seyed Arad Moghadasi; Leroy Versteeg; Christina Nnabuife; Jian-Yuan Li; Xuan Qin; Ying-Chu Chen; John C Faver; Pranavanand Nyshadham; Kiran L Sharma; Banumathi Sankaran; Allison Judge; Zhifeng Yu; Feng Li; Jeroen Pollet; Reuben S Harris; Martin M Matzuk; Timothy Palzkill; Damian W Young

doi:10.1038/s42004-023-00961-y

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.

Authors

Ravikumar Jimmidi^#¹, Srinivas Chamakuri^#², Shuo Lu^#³, Melek Nihan Ucisik¹, Peng-Jen Chen¹, Kurt M Bohren¹, Seyed Arad Moghadasi⁴, Leroy Versteeg^{5

6}, Christina Nnabuife³, Jian-Yuan Li¹, Xuan Qin¹, Ying-Chu Chen¹, John C Faver¹, Pranavanand Nyshadham¹, Kiran L Sharma¹, Banumathi Sankaran⁷, Allison Judge³, Zhifeng Yu¹, Feng Li^{1

3}, Jeroen Pollet^{5

6}, Reuben S Harris^{8

9}, Martin M Matzuk^{1

3}, Timothy Palzkill¹⁰, 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. 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.

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.

Abstract

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