A Pan-Enterovirus Natural Product Inhibitor Targeting a Unique Allosteric Site on the Viral 3C Protease.

IF 2.6 3区 生物学 Q3 MATERIALS SCIENCE, BIOMATERIALS
Shangwu Sun, Qiang Wang, Mengyao Zhu, Xuan Zhang, Xianfang Zhang, Bei Yang
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Abstract

Infections caused by Enterovirus like rhinoviruses, coxsackieviruses, and polioviruses represent a significant public health concern, for which there are no antivirals available yet. The highly conserved viral 3C protease has been the primary target for antiviral development, but competitive inhibitors targeting its active site does not meet expectations in clinical studies. Previously, an unconventional allosteric site is identified on human rhinovirus 14 (HRV14) 3C, representing novel opportunities for pan-enterovirus antivirals development. Here, in silico screening of 143,621 natural products against this allosteric site is performed and 28 candidate molecules are identified, among which dihydromyricetin (DHM) and oridonin-A1 bind to HRV14 3C and allosterically inhibit its protease activity. Moreover, DHM shows minimal cytotoxicity and potent antiviral efficacy against HRV14 infections across different cell models, with selective indexes exceeding 700. Structural analysis and mutagenesis assays further pinpoint key 3C residues essential for DHM binding. Consistent with the high conservation of these residues across Enterovirus genus, DHM broadly binds and efficiently inhibits 3C proteases from not only rhinoviruses, but also coxsackieviruses, enteroviruses and polioviruses. These findings establish DHM as a unique, broad-spectrum allosteric inhibitor of Enterovirus 3C proteases and underscore its potential as a promising candidate for the development of pan-enterovirus antivirals.

一种针对病毒3C蛋白酶独特变构位点的泛肠病毒天然产物抑制剂
肠道病毒如鼻病毒、柯萨奇病毒和脊髓灰质炎病毒引起的感染是一个重大的公共卫生问题,目前还没有抗病毒药物可用。高度保守的病毒3C蛋白酶一直是抗病毒药物开发的主要目标,但针对其活性位点的竞争性抑制剂在临床研究中并未达到预期。此前,在人鼻病毒14 (HRV14) 3C上发现了一个非常规的变抗位点,这为泛肠道病毒抗病毒药物的开发提供了新的机会。本研究对该变构位点的143,621种天然产物进行了硅筛选,鉴定出28种候选分子,其中二氢杨梅素(DHM)和oriidonin - a1与HRV14 3C结合并变构抑制其蛋白酶活性。此外,DHM在不同的细胞模型中对HRV14感染表现出最小的细胞毒性和强大的抗病毒作用,选择指数超过700。结构分析和诱变分析进一步确定了DHM结合所必需的关键3C残基。DHM广泛结合并有效抑制鼻病毒、柯萨奇病毒、肠病毒和脊髓灰质炎病毒的3C蛋白酶,这与这些残基在肠道病毒属中的高度保守性一致。这些发现表明DHM是一种独特的、广谱的肠病毒3C蛋白酶变构抑制剂,并强调了其作为泛肠病毒抗病毒药物开发的潜力。
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
Advanced biology
Advanced biology Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
6.60
自引率
0.00%
发文量
130
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