Mianling Yang, Myoung Kyu Lee, Shenghua Gao, Letian Song, Hye-Yeon Jang, Inseong Jo, Chun-Chiao Yang, Katharina Sylvester, Chunkyu Ko, Shuo Wang, Bing Ye, Kai Tang, Junyi Li, Manyu Gu, Christa E Müller, Norbert Sträter, Xinyong Liu, Meehyein Kim, Peng Zhan
{"title":"利用微型模块化点击化学快速发现独特的 SARS-CoV-2 Mpro 抑制剂,这些抑制剂具有强大的效力和类药物特性。","authors":"Mianling Yang, Myoung Kyu Lee, Shenghua Gao, Letian Song, Hye-Yeon Jang, Inseong Jo, Chun-Chiao Yang, Katharina Sylvester, Chunkyu Ko, Shuo Wang, Bing Ye, Kai Tang, Junyi Li, Manyu Gu, Christa E Müller, Norbert Sträter, Xinyong Liu, Meehyein Kim, Peng Zhan","doi":"10.1002/advs.202404884","DOIUrl":null,"url":null,"abstract":"<p><p>The COVID-19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96- well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (M<sup>pro</sup>) of SARS-CoV-2. Subsequent direct biological screening identifies novel 1,2,3-triazole derivatives as robust M<sup>pro</sup> inhibitors with high anti-SARS-CoV-2 activity. Notably, C5N17B demonstrates sub-micromolar M<sup>pro</sup> inhibitory potency (IC<sub>50</sub> = 0.12 µM) and excellent antiviral activity in Calu-3 cells determined in an immunofluorescence-based antiviral assay (EC<sub>50</sub> = 0.078 µM, no cytotoxicity: CC<sub>50</sub> > 100 µM). C5N17B shows superior potency to nirmatrelvir (EC<sub>50</sub> = 1.95 µM) and similar efficacy to ensitrelvir (EC<sub>50</sub> = 0.11 µM). Importantly, this compound displays high antiviral activities against several SARS-CoV-2 variants (Gamma, Delta, and Omicron, EC<sub>50</sub> = 0.13 - 0.26 µM) and HCoV-OC43, indicating its broad-spectrum antiviral activity. It is worthy that C5N17B retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in M<sup>pro</sup> (EC<sub>50</sub> = 0.26 and 0.15 µM, respectively). Furthermore, C5N17B displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non-covalent multi-site binding mode. In conclusion, these findings substantiate the potential of C5N17B as an up-and-coming drug candidate targeting SARS-CoV-2 M<sup>pro</sup> for clinical therapy.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":null,"pages":null},"PeriodicalIF":14.3000,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Miniaturized Modular Click Chemistry-enabled Rapid Discovery of Unique SARS-CoV-2 M<sup>pro</sup> Inhibitors With Robust Potency and Drug-like Profile.\",\"authors\":\"Mianling Yang, Myoung Kyu Lee, Shenghua Gao, Letian Song, Hye-Yeon Jang, Inseong Jo, Chun-Chiao Yang, Katharina Sylvester, Chunkyu Ko, Shuo Wang, Bing Ye, Kai Tang, Junyi Li, Manyu Gu, Christa E Müller, Norbert Sträter, Xinyong Liu, Meehyein Kim, Peng Zhan\",\"doi\":\"10.1002/advs.202404884\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The COVID-19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96- well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (M<sup>pro</sup>) of SARS-CoV-2. Subsequent direct biological screening identifies novel 1,2,3-triazole derivatives as robust M<sup>pro</sup> inhibitors with high anti-SARS-CoV-2 activity. Notably, C5N17B demonstrates sub-micromolar M<sup>pro</sup> inhibitory potency (IC<sub>50</sub> = 0.12 µM) and excellent antiviral activity in Calu-3 cells determined in an immunofluorescence-based antiviral assay (EC<sub>50</sub> = 0.078 µM, no cytotoxicity: CC<sub>50</sub> > 100 µM). C5N17B shows superior potency to nirmatrelvir (EC<sub>50</sub> = 1.95 µM) and similar efficacy to ensitrelvir (EC<sub>50</sub> = 0.11 µM). Importantly, this compound displays high antiviral activities against several SARS-CoV-2 variants (Gamma, Delta, and Omicron, EC<sub>50</sub> = 0.13 - 0.26 µM) and HCoV-OC43, indicating its broad-spectrum antiviral activity. It is worthy that C5N17B retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in M<sup>pro</sup> (EC<sub>50</sub> = 0.26 and 0.15 µM, respectively). Furthermore, C5N17B displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non-covalent multi-site binding mode. In conclusion, these findings substantiate the potential of C5N17B as an up-and-coming drug candidate targeting SARS-CoV-2 M<sup>pro</sup> for clinical therapy.</p>\",\"PeriodicalId\":117,\"journal\":{\"name\":\"Advanced Science\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":14.3000,\"publicationDate\":\"2024-09-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Advanced Science\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1002/advs.202404884\",\"RegionNum\":1,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advanced Science","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1002/advs.202404884","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Miniaturized Modular Click Chemistry-enabled Rapid Discovery of Unique SARS-CoV-2 Mpro Inhibitors With Robust Potency and Drug-like Profile.
The COVID-19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96- well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (Mpro) of SARS-CoV-2. Subsequent direct biological screening identifies novel 1,2,3-triazole derivatives as robust Mpro inhibitors with high anti-SARS-CoV-2 activity. Notably, C5N17B demonstrates sub-micromolar Mpro inhibitory potency (IC50 = 0.12 µM) and excellent antiviral activity in Calu-3 cells determined in an immunofluorescence-based antiviral assay (EC50 = 0.078 µM, no cytotoxicity: CC50 > 100 µM). C5N17B shows superior potency to nirmatrelvir (EC50 = 1.95 µM) and similar efficacy to ensitrelvir (EC50 = 0.11 µM). Importantly, this compound displays high antiviral activities against several SARS-CoV-2 variants (Gamma, Delta, and Omicron, EC50 = 0.13 - 0.26 µM) and HCoV-OC43, indicating its broad-spectrum antiviral activity. It is worthy that C5N17B retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in Mpro (EC50 = 0.26 and 0.15 µM, respectively). Furthermore, C5N17B displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non-covalent multi-site binding mode. In conclusion, these findings substantiate the potential of C5N17B as an up-and-coming drug candidate targeting SARS-CoV-2 Mpro for clinical therapy.
期刊介绍:
Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.