8TPG

Synthesis, X-Ray Crystallographic and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease

Summary for 8TPG

• Entry DOI: 10.2210/pdb8tpg/pdb
• Descriptor: Non-structural protein 7, (3R)-N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-3-hydroxybutanamide (3 entities in total)
• Functional Keywords: non-peptidic inhibitors, inhibitors, sars-cov-2, main protease, mpro, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34149.02

Authors

Chua, T.K.,Song, Y. (deposition date: 2023-08-04, release date: 2024-01-24, Last modification date: 2024-02-21)

Primary citation

Ashraf-Uz-Zaman, M.,Chua, T.K.,Li, X.,Yao, Y.,Moku, B.K.,Mishra, C.B.,Avadhanula, V.,Piedra, P.A.,Song, Y.
Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease.
Acs Infect Dis., 10:715-731, 2024

PubMed Abstract: 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 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 atom of several epoxide inhibitors. Chloroacetamide inhibitor and epoxide inhibitor were found to inhibit cellular SARS-CoV-2 replication with an EC (half-log reduction of virus titer) of 3 and 5 μM. These compounds represent new pharmacological leads for anti-SARS-CoV-2 drug development.

PubMed: 38192109
DOI: 10.1021/acsinfecdis.3c00565

Experimental method

X-RAY DIFFRACTION (1.692 Å)