符合性灵活性是设计广谱人类诺罗病毒前列腺炎抑制剂的关键因素
Son Pham1, Boyang Zhao1,2, Neetu Neetu1
1Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
bioRxiv : the preprint server for biology
|September 30, 2024
概括
人类诺罗病毒 (HuNoV) 蛋白酶抑制剂的有效性不同. 结构分析显示,由H-G突变引起的GII蛋白酶灵活性会影响抑制剂的功效,指导未来的广谱药物开发.
科学领域:
- 病毒学 病毒学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 人类诺罗病毒 (HuNoV) 构成了全球重大的健康和经济挑战.
- 目前,没有针对HuNoV感染的疫苗或抗病毒药物获得许可.
- HuNoV蛋白酶对于病毒复制至关重要,也是小分子抑制剂的关键标.
研究的目的:
- 阐明小分子抑制剂对HuNoV蛋白酶的作用力差异的结构基础.
- 要了解为什么与GI蛋白酶相比,rupintrivir对GI蛋白酶的效果较差.
主要方法:
- 确定了GI.1,GII.4和GII.3蛋白酶的结晶结构,这些蛋白酶与rupintrivir.vir复合在一起.
- 对蛋白酶突变体进行了酶和抑制研究.
- 分析了蛋白酶活性位点和配体结合的结构差异.
主要成果:
- 胃肠道蛋白酶有一个开放的基质口袋,可以轻松地容纳rupintrivir.
- GII蛋白酶表现出一种灵活的BII-CII循环,该循环重新定位了阿尔金氨-112以结合鲁特维尔.
- 氨酸-112在基质和连接体移位中起作用,影响产品的释放.
结论:
- 由于H-G突变,GII蛋白酶BII-CII循环的灵活性增加是差异抑制剂强度的主要原因.
- 这种固有的灵活性是开发广谱HuNoV蛋白酶抑制剂的关键考虑因素.
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