Retrocyclin reinforcement of pulmonary defenses against viral aerosols

逆环素增强肺部针对病毒气溶胶的防御能力

• 批准号: 7012946
• 负责人: ROBERT IRVING LEHRER
• 金额: $ 28.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012946
• 关键词: aerosols; analog; bioterrorism /chemical warfare; defensins; fluid; human; peptides; phospholipids; proteins; reduction; surfactant

DESCRIPTION (provided by applicant): Introduction: In addition to the a and ¿ defensins produced by human leukocytes and epithelial cells, many nonhuman primates produce ?-defensins, representing a third defensin subfamily. ?-defensins lack potent antibacterial or antifungal activity, but have broad antiviral properties. Retrocyclins are ?-defensins whose structures are based on the sequences of expressed (but untranslated) human ?-defensin pseudogenes. Broad, Long term objectives: To use retrocyclins to enhance pulmonary defenses to viral aerosols. Specific aims. 1. To test retrocyclins against potential viral bioterrorism agents, including Influenza A and B (Orthomyxoviridae), HPIV3 (Paramyxoviridae), West Nile and Yellow Fever virus (Flaviviridae) SARS-CoV (Coronaviridae), Vaccinia (Poxviridae), VEE, an alphavirus (Togaviridae), and Tacaribe virus (Arenaviridae) 2. To examine the interactions of retrocyclins with surfactant proteins SP-A and SP-D. 3. To test the effects actions of RC2 on monolayers and bilayers of pulmonary surfactant phospholipids. Research Design. Retrocyclin-2 (RC-2) and selected analogs will be prepared by solid phase peptide synthesis. Viruses will be tested in vitro by standard plaque reduction and CPE reduction assays. The effects of retrocyclins on the integrity of surfactant phospholipid films will be tested in monolayer systems by using a Langmuir-Blodgett trough, and in bilayer systems by using vesicles composed of surfactant lipids and associated surfactant proteins SP-B and SP-C. Binding of retrocyclins to SP-A and SP-D will be studied by surface plasmon resonance. Effects of retrocyclins on the intrinsic antiviral activity of SP-A and SP-D (and vice versa) will be studied using proteins purified from abattoir-obtained porcine lungs in standard plaque reduction and CPE reduction assays. Health relatedness and Agency Mission. This application is in direct response to PA 04-119. Lay language summary. Many natural viral infections begin with exposure to air that contains viruses. Viral aerosols may also allow bioterrorists to deliver incapacitating viruses. We propose to test the activity of retrocyclins (newly discovered antiviral peptides) against potential viral bioterrorism agents, and to determine their biocompatability with ELF-the thin fluid layer that covers the surface of the pulmonary air sacs.

描述（由申请人提供）： 简介：除了人类白细胞和上皮细胞产生的α和β防御素之外，许多非人灵长类动物还产生β-防御素，代表第三个防御素亚家族。 β-防御素缺乏有效的抗菌或抗真菌活性，但具有广泛的抗病毒特性。逆转录环素是β-防御素，其结构基于表达的（但未翻译的）人β-防御素假基因的序列。广泛、长期的目标：使用逆环素增强肺部对病毒气溶胶的防御能力。具体目标。 1. 测试逆环素针对潜在的病毒生物恐怖因子，包括甲型和乙型流感病毒（正粘病毒科）、HPIV3（副粘病毒科）、西尼罗河病毒和黄热病病毒（黄病毒科）、SARS-CoV（冠状病毒科）、痘苗病毒（痘病毒科）、VEE、甲病毒（披膜病毒科）和 Tacaribe 病毒（沙粒病毒科） 2. 检查逆转录环素与表面活性蛋白 SP-A 和 SP-D 的相互作用。 3. 测试RC2对肺表面活性剂磷脂单层和双层的影响作用。研究设计。 Retrocyclin-2 (RC-2) 和选定的类似物将通过固相肽合成来制备。将通过标准空斑减少和 CPE 减少测定对病毒进行体外测试。逆环素对表面活性剂磷脂膜完整性的影响将在单层系统中使用 Langmuir-Blodgett 槽进行测试，在双层系统中使用由表面活性剂脂质和相关表面活性剂蛋白 SP-B 和 SP-C 组成的囊泡进行测试。将通过表面等离振子共振研究逆环素与 SP-A 和 SP-D 的结合。在标准噬斑减少和 CPE 减少测定中，将使用从屠宰场获得的猪肺中纯化的蛋白质来研究逆环素对 SP-A 和 SP-D 内在抗病毒活性（反之亦然）的影响。健康相关性和机构使命。本申请直接响应 PA 04-119。外行语言总结。许多自然病毒感染都是从接触含有病毒的空气开始的。病毒气溶胶还可能使生物恐怖分子能够传播使人丧失能力的病毒。我们建议测试逆环素（新发现的抗病毒肽）对抗潜在病毒生物恐怖剂的活性，并确定它们与 ELF（覆盖肺气囊表面的薄液体层）的生物相容性。