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

• DOI: 10.1021/acsinfecdis.3c00565
• Publication Date: 2024-01-09T07:17:23Z
• Authors: Md Ashraf-Uz-Zaman; Teck Khiang Chua; Xin Li; Yuan Yao; Bala Krishna Moku; Chandra Bhushan M...; Vasanthi Avadhanula; Pedro A. Piedra; Yongcheng Song
• Keywords: SARS-CoV-2; Acetamides; Humans; COVID-19; Epoxy Compounds; Crystallography, X-Ray; Coronavirus 3C Proteases

Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It caused deaths several million people. The viral main protease (Mpro) is essential for replication and therefore a drug target. Several series covalent inhibitors Mpro were designed synthesized. Structure-activity relationship studies show that (1) chloroacetamide- epoxide-based compounds targeting Cys145 are potent IC50 values as low 0.49 μM (2) Cys44 not nucleophilic inhibitor design. High-resolution X-ray revealed the protein-inhibitor interactions mechanisms inhibition. interest preferably attacks more hindered Cα atom epoxide inhibitors. Chloroacetamide 13 30 found to inhibit cellular an EC68 (half-log reduction virus titer) 3 5 μM. These represent new pharmacological leads anti-SARS-CoV-2 development.