{"title":"含萘-1-乙胺的 SARS-CoV-2 木瓜蛋白酶类小分子抑制剂","authors":"Kouki Shinohara , Takuya Kobayakawa , Kohei Tsuji , Yuki Takamatsu , Hiroaki Mitsuya , Hirokazu Tamamura","doi":"10.1016/j.ejmech.2024.116963","DOIUrl":null,"url":null,"abstract":"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M<sup>pro</sup>) and a papain-like protease (PL<sup>pro</sup>), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL<sup>pro</sup> of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL<sup>pro</sup> showed that GRL-0048 noncovalently interacts with PL<sup>pro</sup>, and there is a newly identified binding pocket in PL<sup>pro</sup>. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds <strong>1</strong>, <strong>2b</strong>, and <strong>3h</strong>, that have more potent inhibitory activity than GRL-0048.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116963"},"PeriodicalIF":6.0000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Naphthalen-1-ylethanamine–containing small molecule inhibitors of the papain-like protease of SARS-CoV-2\",\"authors\":\"Kouki Shinohara , Takuya Kobayakawa , Kohei Tsuji , Yuki Takamatsu , Hiroaki Mitsuya , Hirokazu Tamamura\",\"doi\":\"10.1016/j.ejmech.2024.116963\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M<sup>pro</sup>) and a papain-like protease (PL<sup>pro</sup>), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL<sup>pro</sup> of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL<sup>pro</sup> showed that GRL-0048 noncovalently interacts with PL<sup>pro</sup>, and there is a newly identified binding pocket in PL<sup>pro</sup>. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds <strong>1</strong>, <strong>2b</strong>, and <strong>3h</strong>, that have more potent inhibitory activity than GRL-0048.</div></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":\"280 \",\"pages\":\"Article 116963\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-10-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0223523424008444\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523424008444","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Naphthalen-1-ylethanamine–containing small molecule inhibitors of the papain-like protease of SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (Mpro) and a papain-like protease (PLpro), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PLpro of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PLpro showed that GRL-0048 noncovalently interacts with PLpro, and there is a newly identified binding pocket in PLpro. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds 1, 2b, and 3h, that have more potent inhibitory activity than GRL-0048.
期刊介绍：
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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