Design of Antivirals and Immunogens Targeting Paramyxoviruses

针对副粘病毒的抗病毒药物和免疫原的设计

• 批准号: 9746856
• 负责人: Eva-Maria Strauch
• 金额: $ 37.23万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-16 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9746856
• 关键词: Affinity; Algorithms; Amino Acid Sequence; Antibiotics; Antibody Response; Antigens; Antiviral Agents; Avidity; Back; Bacterial Infections; Binding; Binding Proteins; Binding Sites; Biological Assay; Biological Models; Bronchiolitis; Case Fatality Rates; Cell membrane; Cessation of life; Chimeric Proteins; Crystallization; DNA biosynthesis; DNA sequencing; Data; Data Set; Detection; Development; Diagnostic; Disease Outbreaks; Ebola virus; Elements; Emerging Communicable Diseases; Encephalitis; Epidemic; Epitopes; Evaluation; Family; Family member; Foundations; Generations; Glycoproteins; Goals; HIV; HIV-1; Hendra Virus; Henipavirus; Immune Evasion; Immune system; Infant; Infection; Influenza; Knowledge; Libraries; Mediating; Membrane; Membrane Fusion; Membrane Glycoproteins; Membrane Proteins; Methodology; Methods; Modeling; Molecular; Molecular Conformation; Monitor; Nipah Virus; Paramyxovirus; Pathogenicity; Pattern; Pneumonia; Preparation; Prophylactic treatment; Protein Engineering; Proteins; Protocols documentation; Reagent; Receptor Cell; Resolution; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Role; Scaffolding Protein; Severe Acute Respiratory Syndrome; Site; Structure; Surface; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Virus; Virus Diseases; Work; base; computer design; computer generated; design; genetic selection; improved; influenzavirus; inhibitor/antagonist; innovation; insight; member; neutralizing antibody; next generation; novel; novel therapeutics; receptor; receptor binding; response; vaccine candidate; virus envelope

Abstract Viral infection results in thousands of deaths and an enormous humanitarian burden every year, yet unlike antibiotics for bacterial infection, very few antivirals are available. At present, few methods exist for generating effective antivirals. The increasing availability of atomic resolution structural information of various viral surface proteins promises to chance this. The overall objective of this application is to use the surface glycoproteins of Paramyxoviruses (PMV) as a model system to generate design methodologies that will take advantage of structural features present in a broad range of viruses, resulting in a robust platform for the design of new therapeutics, diagnostics and immunogens for vaccination. PMVs are an ideal model system as their family members have the same fold for receptor recognition yet bind to very different host cell receptors. We recently demonstrated that computational protein design can be used to generate de novo antivirals that broadly neutralize diverse strains of influenza. These computer-generated proteins can also function as highly sensitive diagnostics. Guided by these results, the following specific aims will be pursued: (i) Develop general design strategies to target virus:host cell receptor interactions and design antivirals using Hendra and Nipah Viruses as model systems; (ii) inhibit membrane fusion of RSV by targeting the intermediate fusion states; and (iii) selectively stabilize the pre- and post-fusion state stabilization of the F- protein of RSV and probe their contributions to infectivity and vaccine design. The first aim is based on the observation that many receptor-binding sites of enveloped viruses lay within a recessed pocket, enabling evasion from the immune system. Computational design strategies which specifically target pockets will enable the development a robust algorithm to generate antiviral proteins which bind at these sites. The second aim is based on the hypothesis that the post-fusion structure of viral surface proteins provides the blueprint to targeting their transition state. Small proteins will be designed to molecularly “jam” the 3-helical core structure that is common to most type I fusion proteins and therefore will be provide a general method to inhibit type I fusion proteins, which include viruses such as HIV-1, Ebola, SARS and others. Lastly, the objective of aim three is to simultaneously model the pre- and post-fusion states of the F-protein of RSV to generate variants to favor one state over the other. Variants will be assayed for changes in infectivity. The trapped pre-fusion state stabilized by disfavoring the post-fusion state will provide the basis for a new angle on immunogen design. If successful, data on designs will be fed back into the developed algorithm, leading to rapid development of new antivirals against emerging epidemics.

摘要 病毒感染每年导致数千人死亡，造成巨大的人道主义负担，然而， 与治疗细菌感染的抗生素不同，可用的抗病毒药物很少。目前，很少有方法 产生有效的抗病毒药物越来越多的原子分辨率结构信息的可用性 各种病毒表面蛋白质有望改变这一点。此应用程序的总体目标是使用 副粘病毒（PMV）的表面糖蛋白作为产生设计方法的模型系统 这将利用广泛的病毒中存在的结构特征，从而产生强大的 为疫苗接种设计新的治疗方法、诊断方法和免疫原的平台。PMV是一种 理想的模型系统，因为它们的家族成员具有相同的受体识别折叠， 不同的宿主细胞受体 我们最近证明，计算蛋白质设计可以用来产生从头抗病毒药物 能广泛中和多种流感病毒这些计算机生成的蛋白质也可以发挥作用 作为高度敏感的诊断工具。在这些成果的指导下，将努力实现以下具体目标： 开发针对病毒的一般设计策略：宿主细胞受体相互作用，并使用 亨德拉病毒和尼帕病毒作为模型系统;（ii）通过靶向RSV的膜融合来抑制RSV的膜融合。 （iii）选择性地稳定F-半导体的融合前和融合后状态稳定化; RSV的蛋白质，并探讨其对感染性和疫苗设计的贡献。 第一个目的是基于这样的观察，即包膜病毒的许多受体结合位点位于 在一个凹进的口袋里，能够逃避免疫系统。计算设计策略 其特异性靶向口袋将使得能够开发鲁棒的算法来产生抗病毒药物 在这些位点结合的蛋白质。第二个目标是基于这样的假设，即后融合 病毒表面蛋白的结构提供了靶向其过渡状态的蓝图。小蛋白质将 被设计成分子“堵塞”大多数I型融合蛋白共有的3-螺旋核心结构 因此将提供抑制I型融合蛋白的一般方法，所述I型融合蛋白包括病毒， 如HIV-1、埃博拉、SARS和其他疾病。最后，目标三的目标是同时模拟前- 和RSV的F-蛋白的融合后状态，以产生有利于一种状态而不是另一种状态的变体。 将测定变体的感染性变化。被捕获的融合前状态通过不利于 融合后状态将为免疫原设计的新角度提供基础。如果成功， 设计将反馈到开发的算法中，从而快速开发新的抗病毒药物 对抗新出现的流行病