{"title":"设计源自 GRL0617 的 SARS-CoV-2 木瓜蛋白酶抑制剂:结构-活性关系","authors":"","doi":"10.1016/j.bmc.2024.117909","DOIUrl":null,"url":null,"abstract":"<div><p>The unique and complex structure of papain-like protease (PL<sup>pro</sup>) of the SARS-CoV-2 virus represents a difficult challenge for antiviral development, yet it offers a compelling validated target for effective therapy of COVID-19. The surge in scientific interest in inhibiting this cysteine protease emerged after its demonstrated connection to the cytokine storm in patients with COVID-19 disease. Furthermore, the development of new inhibitors against PL<sup>pro</sup> may also be beneficial for the treatment of respiratory infections caused by emerging coronavirus variants of concern.</p><p>This review article provides a comprehensive overview of PL<sup>pro</sup> inhibitors, focusing on the structural framework of the known inhibitor <strong>GRL0617</strong> and its analogs. We categorize PL<sup>pro</sup> inhibitors on the basis of their structures and binding site: Glu167 containing site, BL2 groove, Val70<sup>Ub</sup> site, and Cys111 containing catalytic site. We summarize and evaluate the majority of <strong>GRL0617</strong>-like inhibitors synthesized so far, highlighting their published biochemical parameters, which reflect their efficacy. Published research has shown that strategic modifications to <strong>GRL0617</strong>, such as decorating the naphthalene ring, extending the aromatic amino group or the orthomethyl group, can substantially decrease the IC<sub>50</sub> from micromolar up to nanomolar concentration range. Some advantageous modifications significantly enhance inhibitory activity, paving the way for the development of new potent compounds. Our review places special emphasis on structures that involve direct modifications to the <strong>GRL0617</strong> scaffold, including piperidine carboxamides and modified benzylmethylnaphthylethanamines (Jun9 scaffold). All these compounds are believed to inhibit the proteolytic, deubiquitination, and deISGylation activity of PL<sup>pro</sup>, biochemical processes linked to the severe progression of COVID-19.</p><p>Finally, we summarize the development efforts for SARS-CoV-2 PL<sup>pro</sup> inhibitors, in detailed structure–activity relationships diagrams. This aims to inform and inspire future research in the search for potent antiviral agents against PL<sup>pro</sup> of current and emerging coronavirus threats.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624003237/pdfft?md5=a44aab9467361c91f0e9ff4b9920c972&pid=1-s2.0-S0968089624003237-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Design of inhibitors of SARS-CoV-2 papain-like protease deriving from GRL0617: Structure–activity relationships\",\"authors\":\"\",\"doi\":\"10.1016/j.bmc.2024.117909\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The unique and complex structure of papain-like protease (PL<sup>pro</sup>) of the SARS-CoV-2 virus represents a difficult challenge for antiviral development, yet it offers a compelling validated target for effective therapy of COVID-19. The surge in scientific interest in inhibiting this cysteine protease emerged after its demonstrated connection to the cytokine storm in patients with COVID-19 disease. Furthermore, the development of new inhibitors against PL<sup>pro</sup> may also be beneficial for the treatment of respiratory infections caused by emerging coronavirus variants of concern.</p><p>This review article provides a comprehensive overview of PL<sup>pro</sup> inhibitors, focusing on the structural framework of the known inhibitor <strong>GRL0617</strong> and its analogs. We categorize PL<sup>pro</sup> inhibitors on the basis of their structures and binding site: Glu167 containing site, BL2 groove, Val70<sup>Ub</sup> site, and Cys111 containing catalytic site. We summarize and evaluate the majority of <strong>GRL0617</strong>-like inhibitors synthesized so far, highlighting their published biochemical parameters, which reflect their efficacy. Published research has shown that strategic modifications to <strong>GRL0617</strong>, such as decorating the naphthalene ring, extending the aromatic amino group or the orthomethyl group, can substantially decrease the IC<sub>50</sub> from micromolar up to nanomolar concentration range. Some advantageous modifications significantly enhance inhibitory activity, paving the way for the development of new potent compounds. Our review places special emphasis on structures that involve direct modifications to the <strong>GRL0617</strong> scaffold, including piperidine carboxamides and modified benzylmethylnaphthylethanamines (Jun9 scaffold). All these compounds are believed to inhibit the proteolytic, deubiquitination, and deISGylation activity of PL<sup>pro</sup>, biochemical processes linked to the severe progression of COVID-19.</p><p>Finally, we summarize the development efforts for SARS-CoV-2 PL<sup>pro</sup> inhibitors, in detailed structure–activity relationships diagrams. This aims to inform and inspire future research in the search for potent antiviral agents against PL<sup>pro</sup> of current and emerging coronavirus threats.</p></div>\",\"PeriodicalId\":255,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-09-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0968089624003237/pdfft?md5=a44aab9467361c91f0e9ff4b9920c972&pid=1-s2.0-S0968089624003237-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0968089624003237\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089624003237","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Design of inhibitors of SARS-CoV-2 papain-like protease deriving from GRL0617: Structure–activity relationships
The unique and complex structure of papain-like protease (PLpro) of the SARS-CoV-2 virus represents a difficult challenge for antiviral development, yet it offers a compelling validated target for effective therapy of COVID-19. The surge in scientific interest in inhibiting this cysteine protease emerged after its demonstrated connection to the cytokine storm in patients with COVID-19 disease. Furthermore, the development of new inhibitors against PLpro may also be beneficial for the treatment of respiratory infections caused by emerging coronavirus variants of concern.
This review article provides a comprehensive overview of PLpro inhibitors, focusing on the structural framework of the known inhibitor GRL0617 and its analogs. We categorize PLpro inhibitors on the basis of their structures and binding site: Glu167 containing site, BL2 groove, Val70Ub site, and Cys111 containing catalytic site. We summarize and evaluate the majority of GRL0617-like inhibitors synthesized so far, highlighting their published biochemical parameters, which reflect their efficacy. Published research has shown that strategic modifications to GRL0617, such as decorating the naphthalene ring, extending the aromatic amino group or the orthomethyl group, can substantially decrease the IC50 from micromolar up to nanomolar concentration range. Some advantageous modifications significantly enhance inhibitory activity, paving the way for the development of new potent compounds. Our review places special emphasis on structures that involve direct modifications to the GRL0617 scaffold, including piperidine carboxamides and modified benzylmethylnaphthylethanamines (Jun9 scaffold). All these compounds are believed to inhibit the proteolytic, deubiquitination, and deISGylation activity of PLpro, biochemical processes linked to the severe progression of COVID-19.
Finally, we summarize the development efforts for SARS-CoV-2 PLpro inhibitors, in detailed structure–activity relationships diagrams. This aims to inform and inspire future research in the search for potent antiviral agents against PLpro of current and emerging coronavirus threats.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.