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对于X因子抑制IgM和辅助介导的腺病毒中和的结构模型

Nicole Wagner¹, Dmitry M Shayakhmetov^2,3,4, Phoebe L Stewart¹

¹Cleveland Center for Membrane and Structural Biology, Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.

|June 28, 2023

概括

结合人类腺病毒血清型5 (HAdv-C5) 的X因子 (FX) 保护它免受自然IgM和补充剂的中和. 这种相互作用阻止IgM激活补充级联,从而增强病毒疗法潜力.

科学领域:

结构生物学是结构生物学.
免疫学免疫学免疫学
病毒学病毒学
基因治疗是一种基因疗法.

背景情况:

人类腺病毒血清型5 (HAdv-C5) 作为瘤治疗性病毒和基因治疗载体显示出治疗前景.
静脉注射HAdv-C5会引起血蛋白相互作用,影响病毒热带,生物分布和免疫反应,导致中和.
HAdv与X因子 (FX) 之间的相互作用增强了肝脏的转导,并防止了补充介导的中和.

研究的目的:

介绍IgM的结构模型和与HAdv-C5.5复合的补充组件 (C1,C4b,C3b).
阐明FX结合抑制HAdv-C5.5的IgM介导中和的机制.
了解补充成分结合如何影响病毒囊稳定性和蛋白VI释放.

主要方法:

用HAdv-C5.5组合生成IgM和补充元件 (C1,C4b,C3b) 的结构模型.
模拟分子动力学以分析病毒囊蛋白和结合分子之间的相互作用.
在HAdv-C5囊上模拟FX和IgM之间的竞争性结合.

主要成果:

结构模型揭示了C3b,基和纤维之间的相互作用,当C3b与HAdv-C5顶点结合时.
这些相互作用稳定了状顶部,并可能阻止病毒溶解蛋白VI的释放,中和病毒.
结合HAdv-C5的FX抑制了IgM介导的补充激活,通过阻止IgM采用中和性曲形状.

结论:

与HAdv-C5的FX相互作用对于保护病毒免受IgM和补充介导的中和至关重要.
结构洞察力解释了FX结合如何阻止IgM启动补充级联,从而抑制病毒中和.
了解这些相互作用为工程腺病毒提供了机械基础,改善了基因疗法的体内性能.

关键词:

腺病毒的病毒.补充 C1 的 C1 补充.补充 C3 补充 C3 补充补充 C4 补充 C4 补充这就是X因子X因子.免疫球蛋白 M 免疫球蛋白分子动力学分子动力学中和化中和化中和化

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