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 protegrin 肽，既可用作预防性传播疾病 (STD) 的局部杀菌剂，又可用作治疗细菌性阴道病 (BV) 的局部治疗剂。 该项目的具体目标是： 1. 设计类 protegrin 分子，使多种 STD 病原体和与细菌性阴道病相关的细菌失活，而不影响正常阴道菌群。 2. 确定 protegrin 的 β 折叠和转角区域如何促进这些活性。 3. 了解 protegrin 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) nonoxynol-9其他表面活性剂。 4. 研究 protegrins 对常见阴道机会主义者白色念珠菌的影响。 5. 检查 protegrin 如何组装成二聚体和寡聚体，并确定这种组装是否以及如何与其抗菌、细胞毒性和溶血特性相关。 Protegrin 是一种小而极其有效的 β-折叠肽，可以迅速灭活许多微生物，包括那些导致大多数性传播细菌感染的微生物。 我们将使用固相肽合成和精确的抗菌测试方法来“微调”protegrin，以用于未来的阴道内应用。 我们的目的是开发类似 protegrin 的肽，这种肽不会影响阴道乳杆菌（例如嗜酸乳杆菌和卷曲乳杆菌），但对白色念珠菌、STD 细菌和与细菌性阴道炎/阴道病相关的菌群具有高度活性。 我们可以通过在具有 15-18 个残基和两个分子内二硫键的 protegrin 中引入一个或两个氨基酸取代来获得这一系列特性。 我们计划产生相对少量的额外 protegrin 变体，并测试它们针对一组 STD 目标生物体的活性。总体而言，这些研究将促进专为阴道内使用而设计的新型含肽局部杀菌剂的开发。 鉴于性病的流行和严重后果，迫切需要能够保护妇女并赋予妇女权力的外用杀菌剂。