通过交叉反应的人类抗体中和马尔堡病毒的结构基础
Takao Hashiguchi1, Marnie L Fusco2, Zachary A Bornholdt2
1Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, 812-8582, Japan.
Cell
|February 28, 2015
概括
一种新型抗体MR78针对马尔堡病毒和埃博拉病毒葡萄糖蛋白的保护区域,阻止细胞进入. 这一发现为开发交叉保护性filovirus免疫疗法和进入抑制剂提供了新的途径.
科学领域:
- 病毒学和结构生物学
- 免疫学 免疫学 免疫学
- 药物发现 药物发现 药物发现
背景情况:
- 菲洛病毒,如马尔堡病毒 (MARV) 和埃博拉病毒 (EBOV),具有表面糖蛋白 (GP),对于细胞附着和进入至关重要.
- 在filovirus GPs中存在显著的序列分歧 (高达70%),阻碍了广泛反应性抗体的发展.
- 之前没有描述过的抗体对不同的filoviruses表现出交叉反应性.
研究的目的:
- 为了确定filovirus糖蛋白的交叉反应抗体识别的结构基础.
- 调查交叉反应抗体作为进入抑制剂和治疗的潜力.
主要方法:
- 确定了马尔堡病毒GP的3.6 Å晶体结构与人类幸存者抗体MR78.8的复合.
- 获得了MR78与埃博拉病毒GP结合的较低分辨率结构.
- 利用小角度X射线散射 (SAXS) 来分析含有粘素的MARV和EBOV的全科医生.
主要成果:
- 抗体MR78识别了一种保存的GP1表位,这种表位在filovirus家族中共享.
- 这种表位被确定为宿主细胞受体NPC1.1的可能结合点.
- MR78有效地阻止了菲洛病毒GP与必不可少的NPC1域C之间的相互作用.
结论:
- 已识别的保存表位和交叉反应抗体MR78为广泛的菲洛病毒免疫疗法提供了一个结构模板.
- 了解MR78结合的结构基础可能会解释为什么在埃博拉病毒研究中以前没有观察到这种抗体.
- 这些发现对于设计新型进入抑制剂和开发针对菲洛病毒感染的有效疫苗或治疗方法至关重要.
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