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广谱抗病毒贝米尼福斯布维尔的激活级联以原子分辨率为特征

Aurélie Chazot¹, Claire Zimberger¹, Mikael Feracci¹

¹Aix Marseille Université, CNRS, AFMB, UMR 7257, Marseille, France.

|August 27, 2024

概括

贝米尼福斯布维尔 (AT-527) 和AT-752需要五种细胞酶来激活AT-9010,这抑制了病毒酶. 这项研究揭示了药物激活途径,并为未来的抗病毒核酸模拟设计提供了信息.

科学领域:

生物化学生物化学
结构生物学结构生物学
病毒学病毒学

背景情况:

贝姆尼福斯布维尔 (AT-527) 和AT-752是正在临床研究中用于治疗RNA病毒感染的瓜诺辛类型.
这些抗病毒药物的代谢激活途径对于它们的有效性至关重要.

研究的目的:

为了阐明贝米尼福斯布维尔和AT-752在细胞上依赖酶的激活途径,使其成为常见的三酸盐形式,AT-9010.
了解AT-9010对病毒酶的选择性抑制的结构基础.

主要方法:

确定了参与AT-9010激活的关键人体酶的晶体结构 (例如,人体海斯蒂丁三核酸结合蛋白1,酸酶1).
利用原子分辨率的功能和结构数据来绘制药物激活过程的地图.
研究了与代谢激活相关的N6-纯素去胺机制.

主要成果:

确定了一组最少的五个细胞酶,这些酶对于贝米尼福斯布维尔/AT-752对AT-9010的激活至关重要,它们发生在一个强制反应序列中.
原子分辨率的晶体结构揭示了在激活途径上的药物蛋白相互作用.
证明AT-9010可以选择性地抑制必要的病毒酶,解释其抗病毒功效.

结论:

该研究描绘了贝米尼福斯布维尔和AT-752的完整酶激活级联,从口服给药到活性三酸盐形式.
对酶前体复合物的结构洞察力为合理的药物设计提供了基础.
这项工作通过考虑细胞激活途径的约束来设计新型抗病毒核酸类型的框架.

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