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病毒蛋白酶的基质识别和分裂机制,核心蛋白酶

Yan Gao^1,2, Xiong Xie^3,4, Xiaoyu Zhang^1,5

¹Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

|April 22, 2025

概括

研究人员阐明了mopox病毒核心蛋白酶 (CorePro) 的结构,揭示了独特的"跳舞对"折叠. 这种结构的洞察力使得能够设计针对天花病毒感染的强效胺抑制剂.

科学领域:

病毒学
结构生物学
医学化学

背景情况:

包括天花和麻疹病毒在内的麻疹病毒对人类健康构成重大威胁.
麻疹病毒核心蛋白酶 (CorePro) 对于病毒的成熟和保存的抗病毒点至关重要.
在此之前,Core^Pro的三维结构是未知的,阻碍了药物的开发.

研究的目的:

为了确定mopox病毒Core^Pro的结构,在它的apo形式和与抑制剂的复合体中.
描述Core^Pro的催化机制和基质结合方式.
设计和开发针对Core^Pro的新型胺抑制剂,用于广泛的抗天花病毒活性.

主要方法:

使用X射线结晶学来确定apompox病毒Core^Pro及其与aloxistatin复合物的结构.
使用天然基质 (I-G18) 的化衍生物进行催化中间状态的表征.
基于结构的药物设计,用于化 (Cys328) 的化弹头.

主要成果:

该结构揭示了Core^Pro形成一个具有独特的"跳舞对"折叠的同位素.
基质结合会导致活性部位的形状从封闭转变为开放.
设计的胺抑制剂表现出强烈的抑制作用 (IC₅₀44. 9 - 100. 3nM) 和广泛的抗天花病毒活性.

结论:

已确定的结构为核心^Pro机制和结构-活动关系提供了关键的见解.
新型胺抑制剂有望开发广泛的抗病毒疗法来对抗天花病毒感染.
这项工作为未来针对保存的天花病毒蛋白酶的抗病毒药物发现奠定了基础.

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