Tanomastat exerts multi-targeted inhibitory effects on viral capsid dissociation and RNA replication in human enteroviruses.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-09-02 DOI:10.1016/j.ebiom.2024.105277

Therese Yien May Lim, Chaitanya K Jaladanki, Yi Hao Wong, Thinesshwary Yogarajah, Hao Fan, Justin Jang Hann Chu

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Abstract

Background: Global cyclical outbreaks of human enterovirus infections has positioned human enterovirus A71 (EV-A71) as a neurotropic virus of clinical importance. However, there remains a scarcity of internationally approved antivirals and vaccines.

Methods: In pursuit of repurposing drugs for combating human enteroviruses, we employed a comprehensive pharmacophore- and molecular docking-based virtual screen targeting EV-A71 capsid protein VP1-4, 3C protease, and 3D polymerase proteins. Among 15 shortlisted ligand candidates, we dissected the inhibitory mechanism of Tanomastat in cell-based studies and evaluated its in vivo efficacy in an EV-A71-infected murine model.

Findings: We demonstrated that Tanomastat exerts dose-dependent inhibition on EV-A71 replication, with comparable efficacy profiles in enterovirus species A, B, C, and D in vitro. Time-course studies suggested that Tanomastat predominantly disrupts early process(es) of the EV-A71 replication cycle. Mechanistically, live virus particle tracking and docking predictions revealed that Tanomastat specifically impedes viral capsid dissociation, potentially via VP1 hydrophobic pocket binding. Bypassing its inhibition on entry stages, we utilized EV-A71 replication-competent, 3D^pol replication-defective, and bicistronic IRES reporter replicons to show that Tanomastat also inhibits viral RNA replication, but not viral IRES translation. We further showed that orally administered Tanomastat achieved 85% protective therapeutic effect and alleviated clinical symptoms in EV-A71-infected neonatal mice.

Interpretation: Our study establishes Tanomastat as a broad-spectrum anti-enterovirus candidate with promising pre-clinical efficacy, warranting further testing for potential therapeutic application.

Funding: MOE Tier 2 grants (MOE-T2EP30221-0005, R571-000-068-592, R571-000-076-515, R571-000-074-733) and A∗STARBiomedical Research Council (BMRC).

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坦诺玛司特对人类肠道病毒的病毒帽解离和RNA复制具有多靶点抑制作用。

背景：全球周期性爆发的人类肠道病毒感染已使人类肠道病毒 A71（EV-A71）成为一种具有重要临床意义的神经性病毒。然而，国际上批准的抗病毒药物和疫苗仍然稀缺：方法：为寻求抗人类肠道病毒药物的再利用，我们采用了基于药理和分子对接的综合虚拟筛选方法，靶向 EV-A71 的荚膜蛋白 VP1-4、3C 蛋白酶和 3D 聚合酶蛋白。在筛选出的15种候选配体中，我们在基于细胞的研究中剖析了坦诺玛司特的抑制机制，并在EV-A71感染的小鼠模型中评估了其体内疗效：我们证明了坦诺玛司特对EV-A71复制具有剂量依赖性抑制作用，在体外对A、B、C和D型肠道病毒具有相似的疗效。时间进程研究表明，坦诺玛司特主要破坏EV-A71复制周期的早期过程。从机理上讲，活病毒粒子跟踪和对接预测显示，坦诺玛司特可能通过 VP1 疏水袋结合，特异性地阻碍病毒荚膜解离。绕过其对进入阶段的抑制作用，我们利用EV-A71复制能力强、3Dpol复制缺陷和双双子IRES报告复制子表明，坦诺玛司特也抑制病毒RNA复制，但不抑制病毒IRES翻译。我们进一步发现，口服坦诺玛司特对EV-A71感染的新生小鼠有85%的保护性治疗效果，并能缓解临床症状：我们的研究确定了坦诺玛司特是一种广谱抗肠病毒候选药物，具有良好的临床前疗效，值得进一步测试其潜在的治疗应用：教育部二级基金（MOE-T2EP30221-0005、R571-000-068-592、R571-000-076-515、R571-000-074-733）和A∗STAR生物医学研究理事会（BMRC）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.