{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ashraf-Uz-Zaman M"],"funding":["National Institute of Allergy and Infectious Diseases","NIAID NIH HHS","National Cancer Institute","NCI NIH HHS","Cancer Prevention and Research Institute of Texas","NIGMS NIH HHS","NIH HHS"],"pagination":["715-731"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10922772"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(2)"],"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<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 <b>13</b> and epoxide inhibitor <b>30</b> 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."],"journal":["ACS infectious diseases"],"pubmed_title":["Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease."],"pmcid":["PMC10922772"],"funding_grant_id":["R21AI159323","R21 AI159323","RP220232","R01 CA266057","P30 GM133893","R01CA266057","S10 OD030246"],"pubmed_authors":["Chua TK","Avadhanula V","Li X","Piedra PA","Yao Y","Mishra CB","Ashraf-Uz-Zaman M","Moku BK","Song Y"],"additional_accession":[]},"is_claimable":false,"name":"Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease.","description":"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 <b>13</b> and epoxide inhibitor <b>30</b> 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2025-04-04T01:37:19.408Z","creation":"2025-04-04T01:37:19.408Z"},"accession":"S-EPMC10922772","cross_references":{"pubmed":["38192109"],"doi":["10.1021/acsinfecdis.3c00565"]}}