抗病毒耐药性的演变捕捉了 chikungunya 病毒包裹糖蛋白之间的短暂的域间功能相互作用
Leandro Battini1,2, Sara A Thannickal3, Malena Tejerina Cibello1
1Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Martín B1650, Argentina.
bioRxiv : the preprint server for biology
|November 28, 2024
概括
奇孔古尼亚病毒 (CHIKV) 进入抑制剂向封膜蛋白E1和E2,可以通过突变克服. 这些突变改变了融合pH值,并影响了病毒感染的动态.
科学领域:
- 病毒学 病毒学
- 结构生物学 结构生物学
- 分子生物学分子生物学
背景情况:
- 病毒的进入依赖于介导宿主细胞膜融合的包膜蛋白.
- 融合性蛋白质共享保存的机制,但中间状态和相互依赖的残留物仍然不太了解.
- Chikungunya 病毒 (CHIKV) 使用 E1-E2 异构体在三元体尖端,由酸性 pH 触发的融合.
研究的目的:
- 研究一种针对CHIKV的新型小分子进入抑制剂的作用机制.
- 了解CHIKV包膜蛋白E1和E2在融合过程中的功能相互作用.
- 探索赋予抗性的突变如何影响病毒适应性和传染性.
主要方法:
- 在抑制器压力下CHIKV的实验进化.
- 对E1和E2包膜蛋白的耐药性突变进行映射.
- 重组病毒的表型特征,包括融合试验和复制研究.
- 模拟分子动力学以评估蛋白质相互作用.
主要成果:
- 在E2和E1.1的远域中发现了赋予耐药性的突变.
- 这种双重突变病毒表现出对融合抑制的耐药性和更高的pH值.
- 单个突变病毒对抑制剂仍然敏感.
- 突变影响了病毒复制,在小鼠中传播,在蚊子中感染率.
结论:
- 鉴定的突变通过克服抑制剂介导的融合阻塞,从而赋予了健康优势.
- 突变的残留物之间存在一个功能链接,调节异构体的形状重排.
- 封膜蛋白功能的微调对于 Chikungunya 病毒感染的建立至关重要.
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