PEPTIDES ACTIVE AGAINST INTRACELLULAR PATHOGENIC DISEASE

有效对抗细胞内致病性疾病的肽

• 批准号: 6180894
• 负责人: MARK L MCLAUGHLIN
• 金额: $ 16.67万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6180894
• 关键词: Brucella abortus; Mycobacterium tuberculosis; antibacterial agents; bactericidal immunity; chemical binding; cytolysis; dosage; drug design /synthesis /production; drug screening /evaluation; host organism interaction; intracellular; laboratory mouse; latent bacterial disease; macrophage; microorganism disease chemotherapy; nonhuman therapy evaluation; synthetic peptide

DESCRIPTION: Intracellular bacteria are responsible for a wide range of chronic and lethal disease in man including tuberculosis and undulant fever (brucellosis), which are caused by Mycobacterium tuberculosis and Brucella abortus, respectively. These bacteria are difficult for the immune system to kill and require lung antibiotic treatment because they hide insight the host's macrophages. For many of these infections, even after disease symptoms have been eliminated, residual live bacteria are often left in macrophage conglomerations known as granulomas. This residual infection is normally harmless, but is responsible for recurrence of infection, which often results in death for immuno-comprised individuals such as those with AIDS. The purpose of the proposed study is to explore a new mechanism for treating intracellular pathogenic diseases by selective lysis of infected macrophages by helical amphipathic peptides. The novel peptides in this work contain large percentages of unnatural alpha, alpha-distributed amino acids, which makes them highly helical even when they are relatively short (10 amino acids). The main hypothesis is that these peptides selectively destroy macrophages infected with intracellular pathogens, releasing the pathogens from their protective niche, thus making them more vulnerable to added antibiotics and the immune response. The mechanism and scope of this novel indirect antimicrobial activity as well as the peptide structural requirements responsible for the observed selectivity will be examined according the following Specific Aims: (1) To probe the mechanism of peptide induced lysis of susceptible macrophage in vitro. Microscopy experiments using labeled bacteria and peptides will determine optimal concentration for selective lysis of infected macrophages and at what concentration peptides bind to and lyse the macrophages. (2) Identification of the most active and selective peptide or peptide mimetic for in vitro and in vivo activity. Starting with the most active peptides currently known the peptide structure and size will be varied to determine what is required for optimal activity and selectivity in lysing of infected macrophages. (3) Optimization of multiple peptide doses and possible synergistic effects of peptides with antibiotics against Brucella abortus and Mycobacterium tuberculosis ex vivo and in vivo. Multiple peptides doses with and without added antibiotics will be studied ex vivo using infected granulomas and in vivo using established mouse model systems.

描述：细胞内细菌负责多种 人类慢性和致命疾病，包括结核病和波状结核病 发烧（布鲁氏菌病），由结核分枝杆菌和 分别为流产布鲁氏菌。这些细菌很难被 免疫系统杀死并需要肺​​部抗生素治疗，因为它们 隐藏宿主巨噬细胞的洞察力。对于许多此类感染，甚至 疾病症状消除后，残留的活菌会被清除。 通常残留在巨噬细胞聚集体中，称为肉芽肿。这 残留感染通常是无害的，但会导致复发 感染，这通常会导致免疫功能低下的人死亡 个人，例如艾滋病患者。拟议研究的目的是 探索治疗细胞内致病性疾病的新机制 通过螺旋两亲选择性裂解受感染的巨噬细胞 肽。这项工作中的新型肽含有很大比例的 非天然的 α、α 分布氨基酸，这使得它们高度 即使它们相对较短（10 个氨基酸），也是螺旋状的。主要 假设这些肽选择性地破坏感染的巨噬细胞 与细胞内病原体一起释放病原体 保护性生态位，从而使它们更容易受到添加抗生素的影响 和免疫反应。 这种新型间接的机制和范围 抗菌活性以及肽结构要求 负责观察到的选择性将根据以下进行检查 具体目的如下：（1）探讨肽诱导的机制 体外裂解敏感巨噬细胞。显微镜实验使用 标记的细菌和肽将确定最佳浓度 选择性裂解受感染的巨噬细胞以及肽的浓度 结合并裂解巨噬细胞。 (2) 识别最活跃的 以及用于体外和体内的选择性肽或肽模拟物 活动。从目前已知的最具活性的肽开始 肽的结构和大小将发生变化以确定所需的内容 以获得裂解受感染巨噬细胞的最佳活性和选择性。 (3) 多种肽剂量的优化和可能的协同作用 肽与抗生素对流产布鲁氏菌的作用 离体和体内结核分枝杆菌。多种肽剂量 添加或不添加抗生素的情况将使用感染的病毒进行离体研究 肉芽肿和体内使用已建立的小鼠模型系统。