Development of Antimicrobial Peptides as Topical Microbicides

我们假设，可以通过肽工程技术发现和改进基于由共同主要研究者实验室开发的抗菌肽数据库（http：//aps.unmc.due/AP/main.html）中收集的天然抗菌肽的新型抗HIV和抗STI局部杀微生物剂。在R21阶段，我们将从数据库中系统地筛选肽，并定义HIV和HSV-2的特异性抑制剂以及广泛的抑制肽。这些活性剂将进一步开发，以了解其范围和抗艾滋病毒的作用机制。在SA 1中鉴定出的上级肽将在SA 2中进行表征，以提供使用各种分子策略在SA 3中继续开发的基本原理，这些策略将导致在有和没有其他小分子杀微生物剂的情况下肽试剂的治疗指数的改善，以便开始有效杀微生物剂产品的开发。本产品将在项目R33部分的动物模型和安全性评估研究中进行配制和评价。我们的目标是生产一种女性控制的预防剂，可用于预防病毒，细菌和真菌生物的性传播，重点是抑制艾滋病毒的传播。研究数据将输入现有的抗菌肽数据库，以方便资助机构、其他研究人员、学生和公众使用。

We hypothesize that novel anti-HIV and anti-STI topical microbicides based on natural antimicrobial peptides collected in the Antimicrobial Peptide Database developed by the co-PI's laboratory (http://aps.unmc.due/AP/main.html) can be discovered and improved through peptide engineering technology. During the R21 phase, we will methodically screen peptides from the database and define specific inhibitors of HIV and HSV-2 as well as broad based inhibitory peptides. These active agents will be further developed in order to understand their range and mechanism of anti-HIV action. Superior peptides identified in SA1 will be characterized in SA2 to provide a rationale for continued development in SA3 using various molecular strategies which will result in the improvement of the therapeutic index of the peptide agents, with and without other small molecule microbicides, in order to begin development of an effective microbicide product. This product will be formulated and evaluated in animal models and safety assessment studies in the R33 portion of the project. Our goal is to produce a female controlled preventative agent which can be utilized to prevent the sexual transmission of viral, bacterial and fungal organisms with a focus on inhibiting the transmission of HIV. The research data will be entered into the existing antimicrobial peptide database to facilitate the use by funding agencies, other researchers, students and the public.