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: 10926320
• 负责人: Alex Compton
• 金额: $ 84.78万
• 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/10926320
• 关键词: 2019-nCoV; Affect; Amphipathic Alpha Helix; Antiviral Therapy; Binding; Cell membrane; Cell physiology; Cells; Cellular Membrane; Cellular Structures; Cholesterol; Development; Ensure; Exhibits; Glean; HIV-1; Half-Life; Human; IFITM1 gene; Immune response; Immunologic Factors; Immunology; Influenza A virus; Integral Membrane Protein; Interferons; Journals; Learning; Lipid Binding; Membrane; Membrane Fusion; Membrane Microdomains; Molecular; Molecular Biology; Nature; Play; Population; Printing; Process; Protein Family; Proteins; Publishing; Receptor Signaling; Reporting; Role; Therapeutic Intervention; Viral; Viral Physiology; Virus; Work; Zika Virus; biophysical properties; gene therapy; human pathogen; in silico; insight; molecular dynamics; new therapeutic target; novel; pathogenic virus; receptor; response; scaffold; therapeutic target; trafficking; tumorigenesis; tumorigenic; tyrosine receptor; viral transmission; 2019-nCoV; Affect; Amphipathic Alpha Helix; Antiviral Therapy; Binding; Cell membrane; Cell physiology; Cells; Cellular Membrane; Cellular Structures; Cholesterol; Development; Ensure; Exhibits; Glean; HIV-1; Half-Life; Human; IFITM1 gene; Immune response; Immunologic Factors; Immunology; Influenza A virus; Integral Membrane Protein; Interferons; Journals; Learning; Lipid Binding; Membrane; Membrane Fusion; Membrane Microdomains; Molecular; Molecular Biology; Nature; Play; Population; Printing; Process; Protein Family; Proteins; Publishing; Receptor Signaling; Reporting; Role; Therapeutic Intervention; Viral; Viral Physiology; Virus; Work; Zika Virus; biophysical properties; gene therapy; human pathogen; in silico; insight; molecular dynamics; new therapeutic target; novel; pathogenic virus; receptor; response; scaffold; therapeutic target; trafficking; tumorigenesis; tumorigenic; tyrosine receptor; viral transmission

We published two articles pertaining to this project in 2020 (Ahi et al., mBio, 2020; Rahman et al., eLife 2020), two articles in 2022 (Rahman et al., Journal of Molecular Biology, 2022; Majdoul et al., Nature Reviews Immunology, 2022), and one preprint so far in 2023 (Shi et al., bioRxiv, 2023). 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 examine how cholesterol binding by IFITM3 directly contributes to its antiviral activities by incorporating in silico analyses using molecular dynamics simulations. We will also assess how lipid binding by IFITM3 affects its trafficking through the cell and protein half-life. In addition, our findings will allow us to better understand the cellular roles played by IFITM3 and related proteins, including its ability to act as a scaffold for receptor tyrosine receptor signaling at lipid rafts in 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年发表了与该项目有关的两篇文章（Ahi等，Mbio，2020； Rahman等，Elife 2020），2022年（Rahman等人，分子生物学杂志，2022; Majdoul et al。，Majdoul et al。我们的工作为IFITM蛋白质的功能以及它们所属的扩展CD225蛋白质家族提供了广泛的见解，并将为开发新的抗病毒疗法提供杠杆作用。值得注意的是，我们确定了IFITM3对多种病毒的抗病毒活性所必需的两亲性α螺旋，包括HIV-1，Zika病毒和流感A A型病毒（Chesarino，Compton等，Embo Reports，2017年）。随后，我们证明了IFITM3改变细胞膜生物物理特性（膜刚度和曲率）的能力（Rahman等，Elife，2020）所必需的。最近，我们证明了两亲性螺旋具有直接的胆固醇结合活性，为其对膜的影响提供了一种可能的解释，以及对IFITM3如何限制膜融合孔形成的合理机制（Rahman等，Rahman等，《分子生物学杂志》，202222222）。现在，我们计划研究IFITM3的胆固醇结合如何通过使用分子动力学模拟中纳入计算机分析来直接促进其抗病毒活性。我们还将评估IFITM3的脂质结合如何影响其通过细胞和蛋白质半衰期的运输。此外，我们的发现将使我们能够更好地理解IFITM3和相关蛋白的细胞作用，包括其充当质膜中脂质筏的受体酪氨酸受体信号传导的脚手架的能力。我们的发现将洞悉该蛋白质家族扮演的肿瘤性作用不佳，并为失活提供治疗靶标。