Pulmonary delivery of a hybrid therapeutic to halt respiratory viral infection

描述(申请人提供)：拟议研究的目标是开发一种混合治疗多肽，可诱导对呼吸道感染的即时和长期保护。这种杂交体的第一部分是C5a受体的生物活性模拟物。这种生物活性多肽(EP67)在体内以有限的C5a受体亚群为靶点。靶向亚群包括树突状细胞，不包括中性粒细胞。EP67与树突状细胞上的C5aR结合可诱导APC活化和细胞因子分泌。当EP67被直接输送到肺部时，它介导了对呼吸道病毒感染的紧急保护。在这个项目的第一个目标中，我们将使用甲型流感作为模型病原体来探索这种保护。这种混合疗法的第二部分是甲型流感融合肽。该融合多肽是所有哺乳动物甲型流感家族中唯一保守的血凝素区域。对这种多肽序列的免疫可以导致对所有哺乳动物甲型流感毒株的完全保护。该项目的第二个目标是一组EP67-融合环杂交肽构建物，用于诱导对系列流感感染的即时和长期保护。该提案的最终目的将研究EP67在靶向向肺部C5a受体承载细胞传递后诱导保护的机制。为了实现这些目标，我们组建了一支拥有免疫学、蛋白质化学、治疗性递送系统、年龄相关免疫缺陷、生物反应修饰、分子生物学和生物统计学专业知识的研究团队。这些目标的成功实现可能会对呼吸道病原体的临床预防和治疗产生革命性的影响，用一种低成本的混合多肽疗法直接肺部注射取代每年一次的疫苗接种，这种疗法可以立即产生终身保护。 公共卫生相关性：该项目的目标是开发一种多肽治疗剂，以介导对呼吸道感染的即时和长期保护。

DESCRIPTION (provided by applicant): The goal of the proposed research is to develop a hybrid therapeutic peptide that induces both immediate and long-lasting protection against respiratory infection. The first portion of this hybrid is a bioactive mimetic of the C5a receptor. This bioactive peptide (EP67) specifically targets a limited subset of C5a receptor bearing cell populations in vivo. The targeted subset includes dendritic cells and excludes neutrophils. Binding of EP67 to the C5aR on dendritic cells induces APC activation and cytokine secretion. When EP67 is delivered directly to the lungs, it mediates emergency protection against respiratory viral infection. In the first aim of this project we will use influenza A as a model pathogen to explore this protection. The second portion of this hybrid therapeutic is the influenza A fusion peptide. The fusion peptide is the only region of hemagglutinin conserved throughout all mammalian influenza A families. Immunity to this peptide sequence could result in complete protection from all strains of mammalian influenza A. The second aim of the project will a panel of EP67-fusion loop hybrid peptide constructs for induction of immediate and long-term protection against serial influenza infection. The final aim of the proposal will study the mechanisms responsible for EP67 induced protection following targeted delivery to C5a receptor bearing cells in the lungs. To accomplish these goals, we have assembled a research team with expertise in immunology, protein chemistry, therapeutic delivery systems, age-related immunodeficiency, biological response modification, molecular biology, and biostatistics. Successful completion of these aims could revolutionize the clinical prevention and treatment of respiratory pathogens, replacing yearly vaccination with direct pulmonary delivery of a low cost hybrid peptide therapeutic that induces immediate, lifelong protection. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a peptide therapeutic agent that mediates immediate and long-term protection against respiratory infection.