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: 9912717
• 负责人: Eva-Maria Strauch
• 金额: $ 37.75万
• 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/9912717
• 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; Detection; Development; Diagnostic; Disease Outbreaks; Ebola; 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; bioweapon; computer design; computer generated; design; genetic selection; improved; influenzavirus; inhibitor/antagonist; innovation; insight; large datasets; 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.

抽象的 病毒感染每年会导致数千人死亡和巨大的人道主义伯纳嫩（Burnen） 与细菌感染的抗生素不同，很少有抗病毒药可用。目前，有很少的方法 产生有效的抗病毒药。原子分辨率的结构信息的可用性不断提高 各种病毒表面蛋白有望机会。该应用程序的总体目的是使用 Paramyxoviruses（PMV）的表面糖蛋白作为生成设计方法的模型系统 这将利用各种病毒中存在的结构特征，从而实现强大的 设计新疗法，诊断和免疫剂的疫苗接种平台。 PMV是一个 理想的模型系统，因为他们的家庭成员具有相同的折叠以识别受体，但与非常结合 不同的主机单元接收器。 我们最近证明，计算蛋白设计可用于生成从头抗病毒药 这广泛消除了潜水员的影响力菌株。这些计算机生成的蛋白质也可以起作用 作为高度敏感的诊断。在这些结果的指导下，将追求以下具体目标：（i） 制定靶向病毒的一般设计策略：宿主细胞受体相互作用和使用使用 Hendra和Nipah病毒作为模型系统； （ii）通过靶向抑制RSV的膜融合 中间融合状态； （iii）选择性稳定F-的融合前后状态稳定 RSV的蛋白质，并探究其对感染和疫苗设计的贡献。 第一个目的是基于观察到的，许多被包膜病毒的受体结合部位放置 在凹陷的口袋内，使免疫系统逃避。计算设计策略 哪个专门针对口袋将使开发能够鲁棒算法生成抗病毒 在这些位点结合的蛋白质。第二个目的是基于以下假设 病毒表面蛋白的结构为靶向其过渡态提供了蓝图。小蛋白会 被设计为分子“果酱”，大多数I型融合蛋白共有的三螺旋核心结构 因此，将提供一种抑制I型融合蛋白的一般方法，其中包括病毒 作为HIV-1，埃博拉，SARS和其他人。最后，目标三的目的是简单地建模 RSV的F蛋白的融合后状态以产生变体以偏爱一个状态而不是另一个状态。 将分配变体的感染变化。被困的前融合状态通过不利 融合后状态将为免疫原设计的新角度提供基础。如果成功，请数据 设计将被馈回发达的算法，从而导致新抗病毒药的快速开发 反对新兴情节。