The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-11-13 DOI:10.1016/j.str.2024.10.025

María Ángeles Márquez-Moñino, Clara M. Santiveri, Patricia de León, Sergio Camero, Ramón Campos-Olivas, M. Ángeles Jiménez, Margarita Sáiz, Beatriz González, José Manuel Pérez-Cañadillas

{"title":"The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity","authors":"María Ángeles Márquez-Moñino, Clara M. Santiveri, Patricia de León, Sergio Camero, Ramón Campos-Olivas, M. Ángeles Jiménez, Margarita Sáiz, Beatriz González, José Manuel Pérez-Cañadillas","doi":"10.1016/j.str.2024.10.025","DOIUrl":null,"url":null,"abstract":"Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site. Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"41 1","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Structure","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.str.2024.10.025","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site. Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

ALS 药物利鲁唑与 SARS-CoV-2 核头状蛋白的 C 端结构域结合并具有抗病毒活性

核蛋白（N）在病毒组装过程中起着至关重要的作用，而且与其他病毒结构蛋白相比不易发生变异，因此成为具有吸引力的药物发现目标。利用基于核磁共振片段的药物发现方法，我们发现 1,3-苯并噻唑-2-胺（BZT）基团是开发 SARS-CoV-2 核苷酸（N）蛋白潜在抗病毒药物的支架。利用核磁共振、X 射线晶体学、抗病毒活性测定和本征荧光测量法对 BZT 衍生物进行的全面表征显示，它们与 N 蛋白的 C 端结构域 (CTD) 的 Arg 259、Trp 330 和 Lys 338 残基结合，与核苷酸结合位点相吻合。我们最有效的化合物比 GTP 和 ALS 药物利鲁唑（也是在筛选过程中发现的）的亲和力稍强，并具有显著的病毒抑制活性。对 218 种基于 BZT 的化合物进行的虚拟筛选发现了一个潜在的扩展结合位点，可用于未来开发新的 SARS-CoV-2 抗病毒药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.