在形分析中分析了 Chikungunya 病毒和 SARS-CoV-2 宏观原体
Vikas Tiwari1, Moira Rachman1, Kenneth Huang1
1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
奇孔古尼亚病毒的NSP3蛋白 (ChikV Mac1) 向宿主蛋白. 结合部位的差异解释了为什么ChikV Mac1的抑制剂比SARS-CoV-2 Mac1少,指导新药设计.
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:
- 奇孔古尼亚病毒NSP3蛋白质的宏观体 (ChikV Mac1) 通过单一ADP核糖酶修改宿主蛋白质,影响这种变异的突变降低了病毒的毒性,使得ChikV Mac1成为潜在的药物标.
- 尽管ChikV Mac1是病毒药物标,但缺乏有效的抑制剂,与结构相似的严重急性呼吸系统综合征冠状病毒2 (SARS-CoV-2) Mac1不同.
研究的目的:
- 为了合理化ChikV Mac1和SARS-CoV-2 Mac1.1之间的连接体结合亲和力的差异.
- 确定导致ChikV Mac1.1药物可抗性较低的结构性和动态因素.
- 设计基于合理化的结合点特征的新奇ChikV Mac1配体.
主要方法:
- 微秒级分子动力学模拟以评估结合点的结构异质性.
- 使用SiteMap和WaterMap进行计算分析,以评估结合部位的可用性和水分子亲和力.
- 与SARS-CoV-2 Mac1相比,holo ChikV Mac1中的蛋白质 - 配体相互作用的分析.
- 基于碎片的配体设计和分子动力学模拟用于验证.
主要成果:
- 与SARS-CoV-2相比,ChikV Mac1表现出更大的apo结合位的形态异质性和较低的药物可用性.
- 水分子在ChikV Mac1的结合体结合部位中结合的亲和力更高,从而降低了结合体亲和力.
- 与SARS-CoV-2相比,在奇孔古尼亚病毒中,与ADP-ribose持续相互作用的Mac1残留物较少.
- 设计的配体显示出 ChikV Mac1 抑制的潜力,通过分子动力学验证.
结论:
- 与SARS-CoV-2 Mac1.1相比,结合部位动态,水占用率和残留物相互作用的差异解释了与ChikV Mac1相比,对ChikV Mac1的联结体亲和力较低.
- 这项研究为设计强效ChikV Mac1抑制剂提供了合理的基础.
- 开发的片段生长策略和验证的配体为奇孔古尼亚病毒治疗提供了一个有希望的起点.
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