Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease.

Autor:	Ashraf-Uz-Zaman M; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States., Chua TK; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States., Li X; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States., Yao Y; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States., Moku BK; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States., Mishra CB; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States., Avadhanula V; Department of Molecular Virology & Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States., Piedra PA; Department of Molecular Virology & Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States., Song Y; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2024 Feb 09; Vol. 10 (2), pp. 715-731. Date of Electronic Publication: 2024 Jan 08.
DOI:	10.1021/acsinfecdis.3c00565
Abstrakt:	Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It has caused deaths of several million people. The viral main protease (Mpro) is essential for SARS-CoV-2 replication and therefore a drug target. Several series of covalent inhibitors of Mpro were designed and synthesized. Structure-activity relationship studies show that (1) several chloroacetamide- and epoxide-based compounds targeting Cys145 are potent inhibitors with IC 50 values as low as 0.49 μM and (2) Cys44 of Mpro is not nucleophilic for covalent inhibitor design. High-resolution X-ray studies revealed the protein-inhibitor interactions and mechanisms of inhibition. It is of interest that Cys145 preferably attacks the more hindered C α atom of several epoxide inhibitors. Chloroacetamide inhibitor 13 and epoxide inhibitor 30 were found to inhibit cellular SARS-CoV-2 replication with an EC 68 (half-log reduction of virus titer) of 3 and 5 μM. These compounds represent new pharmacological leads for anti-SARS-CoV-2 drug development.
Databáze:	MEDLINE
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