PROTEGRIN DESIGN

蛋白质设计

• 批准号: 6340685
• 负责人: ROBERT IRVING LEHRER
• 金额: $ 15.97万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6340685
• 关键词: Candida albicans; antibiotics; clinical research; disease /disorder prevention /control; drug design /synthesis /production; drug interactions; drug screening /evaluation; endopeptidases; human subject; nonoxynol 9; peptides; protein structure function; sexually transmitted diseases; topical drug application; vaginitis

Our long term goal is to design protegrin peptides that will be used both as topical microbicides to prevent sexually transmitted diseases (STDs) and as topical therapeutics to remediate bacterial vaginosis (BV). The Specific Aims of this project are: 1. To design protegrin-like molecules that inactivate multiple STD agents and the bacteria associated with bacterial vaginosis, without affecting normal vaginal flora. 2. To determine how the beta-sheet and turn regions of protegrins contribute to these activities. 3. To learn how protegrins interact with factors relevant to their use as topical microbicides, including a) host proteins, peptides, peptides and cells; b) host and microbial proteases; c) nonoxynol-9 other surfactants. 4. To study the effects of protegrins on C. albicans a frequent vaginal opportunist. 5. To examine how protegrins assemble into dimers and oligomers, and ascertain if and how such assemble relates to their antimicrobial, cytotoxic and hemolytic properties. Protegrins are small, exceptionally potent, beta-sheet peptides that rapidly inactivate many microbes, including those responsible for most sexually transmitted bacterial infections. We will use solid-phase peptide synthesis and precise methods of antimicrobial testing to "fine tune" protegrins for future intravaginal application. Our intent is to develop protegrin-like peptides that do not affect vaginal lactobacilli (e.g., L. acidophilus and L. crispatus), but are highly active against C. albicans, STD bacteria, and the flora associated with bacterial vaginitis/vaginosis. We can obtain this constellation of properties by introducing one or two amino acid substitutions into protegrins with 15-18 residues and two intramolecular disulfide bonds. We plan to generate a relatively small number of additional protegrin variants and to test their activity against a panel of STD target organisms. Overall, these studies will facilitate the development of novel, peptide- containing topical microbicides that are designed specifically for intravaginal use. Given the prevalence and serious consequences of STDs, topical microbicides that can protect and empower women are urgently needed.

我们的长期目标是设计蛋白肽，这些肽既可以用作局部菌心，以防止性传播疾病（STD）和局部疗法来补救细菌性阴道病（BV）。 该项目的具体目的是：1。设计灭活多种性病药物和与细菌性阴道病相关的细菌，而不会影响正常的阴道菌群。 2。确定beta表和转向质蛋白的区域如何促进这些活动。 3。要了解protegrins如何与与其用作局部杀菌剂相关的因素相互作用，包括a）宿主蛋白，肽，肽和细胞； b）宿主和微生物蛋白酶； c）非氧合-9其他表面活性剂。 4。研究prot蛋白对白色念珠菌的影响，是一种频繁的阴道机会主义。 5。检查protegrins如何组装成二聚体和低聚物，并确定这种组装是否与它们的抗菌，细胞毒性和溶血性能有关。 protins很小，非常有效的β-片肽迅速使许多微生物（包括负责大多数性传播细菌感染的人）迅速失活。 我们将使用固相肽的合成和抗菌测试的精确方法来“微调” protegin，以进行未来的阴道内应用。 我们的目的是开发不影响阴道乳酸杆菌（例如L. copophilus and L. crispatus）的原蛋白样肽，但对白色念珠菌，性病细菌以及与细菌性阴道炎/阴道病相关的植物群具有很高的活性。 我们可以通过将一个或两个氨基酸取代引入具有15-18个残基和两个分子内二硫键键中来获得该性质的星座。 我们计划生成相对少量的其他原素蛋白变体，并针对一系列STD靶生物测试其活性。总体而言，这些研究将促进专门为阴道内使用而设计的新型肽 - 含有局部菌皮的新型肽。 鉴于性病的患病率和严重后果，迫切需要保护和赋予妇女权力的局部杀菌剂。