tetano
Editor, Senior Moderator
ACS Infect Dis
. 2024 Jan 8.
doi: 10.1021/acsinfecdis.3c00565. Online ahead of print. Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease
Md Ashraf-Uz-Zaman[SUP] 1 [/SUP], Teck Khiang Chua[SUP] 1 [/SUP], Xin Li[SUP] 1 2 [/SUP], Yuan Yao[SUP] 1 [/SUP], Bala Krishna Moku[SUP] 1 [/SUP], Chandra Bhushan Mishra[SUP] 1 [/SUP], Vasanthi Avadhanula[SUP] 3 [/SUP], Pedro A Piedra[SUP] 3 [/SUP], Yongcheng Song[SUP] 1 2 [/SUP]
Affiliations
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[SUB]50[/SUB] 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[SUB]α[/SUB] atom of several epoxide inhibitors. Chloroacetamide inhibitor 13 and epoxide inhibitor 30 were found to inhibit cellular SARS-CoV-2 replication with an EC[SUB]68[/SUB] (half-log reduction of virus titer) of 3 and 5 μM. These compounds represent new pharmacological leads for anti-SARS-CoV-2 drug development.
Keywords: SARS-CoV-2; X-ray crystallography; antiviral agents; enzyme inhibitors; main protease.
. 2024 Jan 8.
doi: 10.1021/acsinfecdis.3c00565. Online ahead of print. Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease
Md Ashraf-Uz-Zaman[SUP] 1 [/SUP], Teck Khiang Chua[SUP] 1 [/SUP], Xin Li[SUP] 1 2 [/SUP], Yuan Yao[SUP] 1 [/SUP], Bala Krishna Moku[SUP] 1 [/SUP], Chandra Bhushan Mishra[SUP] 1 [/SUP], Vasanthi Avadhanula[SUP] 3 [/SUP], Pedro A Piedra[SUP] 3 [/SUP], Yongcheng Song[SUP] 1 2 [/SUP]
Affiliations
- PMID: 38192109
- DOI: 10.1021/acsinfecdis.3c00565
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[SUB]50[/SUB] 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[SUB]α[/SUB] atom of several epoxide inhibitors. Chloroacetamide inhibitor 13 and epoxide inhibitor 30 were found to inhibit cellular SARS-CoV-2 replication with an EC[SUB]68[/SUB] (half-log reduction of virus titer) of 3 and 5 μM. These compounds represent new pharmacological leads for anti-SARS-CoV-2 drug development.
Keywords: SARS-CoV-2; X-ray crystallography; antiviral agents; enzyme inhibitors; main protease.