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新型柯萨奇病毒 A9 衣壳结合物的 SAR 分析。

SAR Analysis of Novel Coxsackie virus A9 Capsid Binders.

机构信息

Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy.

Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, & Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland.

出版信息

J Med Chem. 2024 Oct 10;67(19):17144-17161. doi: 10.1021/acs.jmedchem.4c00701. Epub 2024 Sep 18.

Abstract

Enterovirus infections are common in humans, yet there are no approved antiviral treatments. In this study we concentrated on inhibition of one of the (EV-B), namely Coxsackievirus A9 (CVA9), using a combination of medicinal chemistry, virus inhibition assays, structure determination from cryogenic electron microscopy and molecular modeling, to determine the structure activity relationships for a promising class of novel -phenylbenzylamines. Of the new 29 compounds synthesized, 10 had half maximal effective concentration (EC) values between 0.64-10.46 μM, and of these, 7 had 50% cytotoxicity concentration (CC) values higher than 200 μM. In addition, this new series of compounds showed promising physicochemical properties and act through capsid stabilization, preventing capsid expansion and subsequent release of the genome.

摘要

肠道病毒感染在人类中很常见,但目前尚无批准的抗病毒治疗方法。在这项研究中,我们专注于使用组合药物化学、病毒抑制测定、低温电子显微镜结构测定和分子建模来抑制一种肠道病毒(EV-B),即柯萨奇病毒 A9(CVA9),以确定一类有前途的新型 - 苯基苄基胺的结构活性关系。在所合成的 29 种新化合物中,有 10 种的半数最大有效浓度(EC)值在 0.64-10.46 μM 之间,其中 7 种的 50%细胞毒性浓度(CC)值高于 200 μM。此外,这一系列新化合物表现出有前途的物理化学性质,并通过衣壳稳定作用发挥作用,防止衣壳扩张和随后基因组的释放。

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