Design of peptide entry inhibitors and delivery systems to target emerging henipa

副粘病毒导致重要的人类疾病，这些疾病对全球疾病和死亡率有很大贡献。 两种人畜共患副粘病毒Hendra(HEV)和Nipah(Niv)因其致命性而引起紧急关注 和可传播性。HEV和NIV通过与细胞表面受体结合而启动感染，并直接融合 随着细胞膜的进入。受体结合分子(G)触发病毒融合蛋白(F)与其 活性状态和F蛋白的构象变化驱动融合。七肽重复序列(HR)的分子模拟 HEV F区可以阻止F达到融合就绪的构象，并防止感染。我们发现 异源(副流感3)多肽作为抗HEV/NIV比同源多肽更有效。 我们提出了一个独特的组合：(1)分子的实验和结构分析 融合和进入抑制机制，以设计最佳的抑制剂；(2)动物模型研究，以测试 建议用于预防感染的抗病毒药物；(3)改善给药系统的生物工程方法 前景看好的抗病毒药物。多学科协作团队，带来独特的专业知识，协同研究： 1.戊型肝炎病毒和新城疫病毒F蛋白的构象变化：设计有效多肽的基础研究 1.1同型和异型HRC抑制融合机制的结构分析 多肽。通过将实验信息与我们对6Hb的X射线晶体结构的分析相结合 HPIV3F、HEV F和HPIV3/HEV嵌合6HBs，抑制肽的作用机制将是 在结构上和生物物理上进行了探索。 1.2基于晶体结构数据的改进多肽的设计和测试。 2.多肽对活体病毒感染的保护作用。有效多肽(目标1)将 在金黄地鼠模型上测试它们抵御HEV和NiV感染的能力 急性HEV/NIV感染。治疗以及暴露前和暴露后的预防将被讨论。 微粒将被设计成提供最有希望的抑制剂的持续输送，以探索 假设缓释可以提高体内的抗病毒效果，并提供了一种临床策略 在危机情况下是可行的。来自目标2的反馈将直接导致目标1中的新实验。 这些结果将导致：(1)对病毒融合、进入和感染的分子机制有新的认识。 多肽抑制剂的作用机制；(2)可广泛用于抗病毒药物的持续给药系统 可应用和临床相关；(3)体内抗病毒策略的验证，并确定现实 候选抗病毒肽。鉴于副粘病毒的重要性，这一结果将具有重要意义。 对人类健康和潜在的广泛适用性的新平台，除了具体 这些新出现的人畜共患病病原体的临床/生物防御相关性。

Paramyxoviruses cause important human illnesses that contribute significantly to global disease and mortality. Two zoonotic paramyxoviruses, Hendra (HeV) and Nipah (NiV), are of urgent concern due to their lethal and transmissible nature. HeV and NiV initiate infection by binding to cell surface receptors, and fuse directly with the cell membrane to enter. The receptor-binding molecule (G) triggers the viral fusion protein (F) to its active state, and conformational changes in F protein drive fusion. Molecular mimics of the heptad repeat (HR) regions of HeV F can prevent F from reaching fusion-ready conformation, and prevent infection. We found that a heterologous (parainfluenza 3) peptide is more effective than the homologous peptide as an anti-HeV/NiV. We propose a distinctive combination of: (1) experimental and structural analysis of the molecular mechanisms of fusion and entry inhibition, to design optimal inhibitors; (2) animal model studies to test the proposed antivirals for protection from infection; (3) bioengineering approaches to improve delivery systems for promising antivirals. A multidisciplinary collaborative team, bringing unique expertise, synergizes to study: 1. Conformational changes in HeV and NiV F-protein: Basic research to design effective peptides. 1.1 Structural analysis of the mechanism of fusion inhibition by homotypic and heterotypic HRC peptides. By combining experimental information with analysis of our X-ray crystal structures of the 6HBs of HPIV3 F, HeV F and HPIV3/HeV chimeric 6HBs, the mechanism of action of inhibitory peptides will be explored structurally and biophysically. 1.2 Design and testing of improved peptides based on crystal structure data. 2. Effectiveness of the peptides to protect from live viral infection in vivo. Effective peptides (aim 1) will be tested for their ability to protect against infection with HeV and NiV infection in the golden hamster model of acute HeV/NiV infection. Treatment as well as pre- and post-exposure prophylaxis will be addressed. Microparticles will be engineered to provide sustained delivery of the most promising inhibitors, to explore the hypothesis that sustained release can improve antiviral efficacy in vivo and provide a clinical strategy that would be feasible for crisis situations. Feedback from aim 2 will lead directly to new experiments in aim 1. The results will lead to: (1) New understanding about the molecular mechanisms of virus fusion, entry, and mechanisms of action of peptide inhibitors; (2) sustained delivery systems for antivirals that may be broadly applicable and clinically relevant; (3) validation of an antiviral strategy in vivo, and identification of realistic candidate antiviral peptides. The results will be significant in light of the importance of paramyxoviruses to human health and the potential broad applicability of the new platforms, in addition to the specific clinical/biodefense relevance of these emerging zoonotic pathogens.