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

Autor: Jimmidi R; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Chamakuri S; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA. srinivas.chamakuri@bcm.edu., Lu S; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA., Ucisik MN; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Chen PJ; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Bohren KM; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Moghadasi SA; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455, USA., Versteeg L; Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, 77030, USA.; Center for Vaccine Development, Texas Children's Hospital, 1102 Bates Street, Houston, Texas, 77030, USA., Nnabuife C; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA., Li JY; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Qin X; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Chen YC; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Faver JC; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Nyshadham P; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Sharma KL; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Sankaran B; Department of Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, California, 94720, USA., Judge A; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA., Yu Z; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA., Li F; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA., Pollet J; Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, 77030, USA.; Center for Vaccine Development, Texas Children's Hospital, 1102 Bates Street, Houston, Texas, 77030, USA., Harris RS; Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, Texas, 78229, USA.; Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, Texas, 78229, USA., Matzuk MM; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA., Palzkill T; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA. timothyp@bcm.edu., Young DW; Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, 77030, USA. damian.young@bcm.edu.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, 77030, USA. damian.young@bcm.edu.
Jazyk: angličtina
Zdroj: Communications chemistry [Commun Chem] 2023 Aug 04; Vol. 6 (1), pp. 164. Date of Electronic Publication: 2023 Aug 04.
DOI: 10.1038/s42004-023-00961-y
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje