Pulmonary delivery of a hybrid therapeutic to halt respiratory viral infection

肺部输送混合疗法以阻止呼吸道病毒感染

• 批准号: 8026352
• 负责人: JOY A. PHILLIPS
• 金额: $ 31.11万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026352
• 关键词: Adjuvant; Agonist; Amino Acids; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Binding; Biological; Biometry; Bioterrorism; C5a anaphylatoxin receptor; Cells; Cleaved cell; Clinical; Communicable Diseases; Cytokine Activation; Cytoplasm; Dendritic Cells; Disease Outbreaks; Dose; Emergency Situation; Endosomes; Epitopes; Family; Goals; Hemagglutinin; Humoral Immunities; Hybrids; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunology; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza Hemagglutinin; Influenza prevention; Interferon Type II; Interleukin-6; Lung; Mediating; Modeling; Modification; Molecular Biology; Mus; National Institute of Allergy and Infectious Disease; Pathway Analysis; Peptide Hydrolases; Peptides; Population; Prevention; Prevention strategy; Prophylactic treatment; Protein Chemistry; Protein Precursors; Research; Respiratory Tract Infections; Signal Pathway; Site; Surface; System; TNF gene; Testing; Therapeutic; Therapeutic Agents; Time; Vaccination; Vaccines; Viral; Virus; Virus Diseases; age related; aged; base; cost; cytokine; in vivo; member; mimetics; neutrophil; pandemic disease; pathogen; protein aminoacid sequence; receptor; receptor mediated endocytosis; respiratory; response; targeted delivery

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.

描述（由申请人提供）：拟议研究的目标是开发一种混合治疗肽，可诱导对呼吸道感染的即时和持久保护。该杂交体的第一部分是C5a受体的生物活性模拟物。这种生物活性肽（EP67）在体内特异性靶向有限的C5a受体承载细胞群。目标亚群包括树突状细胞，不包括中性粒细胞。树突状细胞上EP67与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。在本项目的第一个目标中，我们将以甲型流感作为模型病原体来探索这种保护作用。这种混合疗法的第二部分是甲型流感融合肽。融合肽是血凝素在所有哺乳动物甲型流感家族中唯一保守的区域。对该肽序列的免疫可导致对所有哺乳动物甲型流感病毒株的完全保护。该项目的第二个目标是构建ep67融合环杂交肽面板，以诱导对系列流感感染的即时和长期保护。该提案的最终目的是研究EP67靶向递送至肺部C5a受体承载细胞后诱导保护的机制。为了实现这些目标，我们组建了一支在免疫学、蛋白质化学、治疗递送系统、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方面具有专业知识的研究团队。成功完成这些目标可能会彻底改变呼吸道病原体的临床预防和治疗，用直接肺输送低成本的混合肽治疗取代每年的疫苗接种，从而产生即时的终身保护。