{"title":"Structure-Based Optimization and Biological Evaluation of SARS-CoV-2 3CLpro Covalent Inhibitors","authors":"Nicolas, Moitessier, Guanyu, Wang, Julia, Stille, Richard, Boulon, Christopher, Hennecker, Xiaocong, Zhang, Nicole, Blaine, Steven, Laplante, Anthony, Mittermaier","doi":"10.26434/chemrxiv-2024-091mt","DOIUrl":null,"url":null,"abstract":"The global emergence of COVID-19, caused by SARS-CoV-2, has underscored the critical need for effective antivirals against coronaviruses. The 3-chymotrypsin-like protease (3CLpro) of coronavirus has been a primary target for drug development due to its critical role across various coronaviruses. Following our initial report, this study focuses on the structure-based optimization of 3CLpro covalent inhibitors. With the guidance of molecular docking and covalent binding parameters measured from an innovative isothermal titration calorimetry-kinetic competition (ITC-KC) assay, we optimized and synthesized series of potent covalent inhibitors with antiviral activity in cell-based assays.","PeriodicalId":9813,"journal":{"name":"ChemRxiv","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemRxiv","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.26434/chemrxiv-2024-091mt","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
The global emergence of COVID-19, caused by SARS-CoV-2, has underscored the critical need for effective antivirals against coronaviruses. The 3-chymotrypsin-like protease (3CLpro) of coronavirus has been a primary target for drug development due to its critical role across various coronaviruses. Following our initial report, this study focuses on the structure-based optimization of 3CLpro covalent inhibitors. With the guidance of molecular docking and covalent binding parameters measured from an innovative isothermal titration calorimetry-kinetic competition (ITC-KC) assay, we optimized and synthesized series of potent covalent inhibitors with antiviral activity in cell-based assays.
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