Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry

病毒进入细胞的机制和限制进入的抗病毒屏障

• 批准号: 10702668
• 负责人: Alex Compton
• 金额: $ 67.15万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702668
• 关键词: Address; Affect; Amino Acids; Amphipathic Alpha Helix; Antiviral Therapy; Binding; Categories; Cell fusion; Cell membrane; Cell-Matrix Junction; Cells; Cellular Membrane; Cholesterol; Development; Evolution; Exhibits; Glean; Glycoproteins; Goals; HIV-1; Human; IFITM1 gene; Infection; Influenza A virus; Integral Membrane Protein; Interferons; Journals; Measures; Mediating; Membrane; Membrane Fusion; Molecular Biology; Murine leukemia virus; Mutation; Oncogenic; Pathogenicity; Physiological; Play; Process; Protein Family; Proteins; Publishing; RNA Viruses; Reporting; Retroviridae; Role; Route; Signal Transduction; System; Therapeutic Intervention; Viral Proteins; Virion; Virus; Work; Zika Virus; base; biophysical properties; cell type; experimental study; gene therapy; insight; mutant; novel; preservation; scaffold; therapeutic target; transmission process; tumorigenic

We published two articles pertaining to this project in 2020 (Ahi et al., mBio, 2020; Rahman et al., eLife 2020) and one article in 2022 (Rahman et al., Journal of Molecular Biology, 2022). Our work provides extensive insight into the function of IFITM proteins as well as the extended CD225 protein family to which they belong and will provide leverage for the development of new antiviral therapies. Notably, we identified an amphipathic alpha helix that is required for the antiviral activity of IFITM3 against multiple viruses, including HIV-1, Zika virus, and Influenza A virus (Chesarino, Compton et al. EMBO Reports, 2017). Subsequently, we showed that the amphipathic helix is required for the ability of IFITM3 to alter the biophysical properties of cellular membranes (membrane rigidity and curvature) (Rahman et al., eLife, 2020). Most recently, we demonstrated that the amphipathic helix exhibits direct cholesterol binding activity, providing a possible explanation for its impacts on membranes and a plausible mechanism for how IFITM3 restricts membrane fusion pore formation (Rahman et al., Journal of Molecular Biology, 2022). We now plan to directly measure cholesterol binding by IFITM3 contributes to its effect on membrane rigidity, a feature that is functionally tied to its capacity to inhibit virus entry. Furthermore, we plan to assess the functional role played by the amphipathic helix in the oncogenic functions of IFITM3, including its ability to act as a scaffold for PI3K signaling at the plasma membrane. Our findings will provide insight into the poorly characterized tumorigenic roles played by this family of proteins and provide therapeutic targets for inactivation.

我们在2020年发表了两篇与该项目有关的文章（Ahi et al.，mBio，2020; Rahman等人，eLife 2020）和2022年的一篇文章（Rahman等人，Journal of Molecular Biology，2022）。我们的工作为IFITM蛋白的功能提供了广泛的见解， 以及它们所属的扩展的CD 225蛋白家族，并将为 新的抗病毒疗法的发展。值得注意的是，我们发现了一种两亲性的α螺旋 这是IFITM 3抗多种病毒的抗病毒活性所必需的，包括 HIV-1、寨卡病毒和甲型流感病毒（Chesarino，Compton et al. EMBO Reports，2017）。 随后，我们发现两亲性螺旋是IFITM 3的能力所必需的， 改变细胞膜的生物物理特性（膜的硬度和曲率） （Rahman等人，eLife，2020年）。最近，我们证明了两亲性螺旋 显示出直接的胆固醇结合活性，为它的影响提供了可能的解释。 对膜的影响以及IFITM 3如何限制膜融合孔形成的合理机制 （Rahman等人，Journal of Molecular Biology，2022）。我们现在计划直接测量 IFITM 3与胆固醇的结合有助于其对膜刚性的影响，这一特征 在功能上与其抑制病毒进入的能力有关。此外，我们计划评估 两亲性螺旋在IFITM 3的致癌功能中所起的功能作用， 包括其作为质膜上PI 3 K信号传导的支架的能力。我们 研究结果将提供深入了解这一点所发挥的不良特征的致瘤作用。 蛋白质家族，并提供灭活的治疗靶点。