PROTEGRIN DESIGN

我们的长期目标是设计保护素肽，其将用作局部杀微生物剂以预防性传播疾病（STD）和用作局部治疗剂以修复细菌性阴道病（BV）。 该项目的具体目标是：1。 设计一种能抑制多种性病病原体和细菌性阴道病相关细菌的protegrin样分子，而不影响正常的阴道植物群。 2.为了确定如何β折叠和turn区域的protegrins有助于这些活动。3. 了解protegrins如何与其用作局部杀微生物剂的相关因素相互作用，包括a）宿主蛋白质、肽、肽和细胞; B）宿主和微生物蛋白酶; c）壬苯醇醚-9其他表面活性剂。4.研究protegrins对C.白色念珠菌是常见的阴道机会主义者。 5.研究protegrins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。Protegrins是一种小的，非常有效的β折叠肽，可以迅速杀死许多微生物，包括那些负责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微生物测试方法来“微调”protegrins用于未来的阴道内应用。 我们的目的是开发不影响阴道乳杆菌的保护素样肽（例如，L.嗜酸乳杆菌和L. crispatus），但对C.白色念珠菌、STD细菌和与细菌性阴道炎/阴道病相关的植物群。 我们可以通过在具有15-18个残基和两个分子内二硫键的protegrins中引入一个或两个氨基酸取代来获得这种性质。 我们计划产生相对少量的其他保护蛋白变体，并测试它们对一组STD靶生物的活性。总的来说，这些研究将有助于开发新的，含肽的局部杀微生物剂，专门设计用于阴道内使用。 鉴于性传播疾病的流行和严重后果，迫切需要能够保护妇女和赋予妇女权力的局部杀微生物剂。

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.