Discovery of drugs for use in the treatment and prevention of HIV infection using

描述（由申请人提供）：天然产物仍然是主要的治疗剂。然而，它们在创造衍生品方面存在困难，而且它们也难以供应。衍生物在优化性质方面非常重要，例如毒性或溶解度，这对治疗学的发展至关重要。近年来，利用天然产物生物合成基因的基因工程技术创建衍生物文库已变得越来越流行。即使在最好的图书馆中，衍生品的数量也只有几百个或几千个。最近，我们发现了一种进化途径，它可能被用来产生多达数十亿的衍生物。这些化合物可以快速“进化”以改善所需的性能，同时最大限度地减少不必要的影响。我们已经开发了一个系统，在这个系统中，新的活性可以在几天到几周的时间内从药理学上进行优化，探索各种非自然的天然产品。在这个项目中，我们将开发这个系统来生产抗hiv化合物，以便快速开发。该建议的进化特征将允许先导物快速优化，以克服药物开发中的常见问题。我们的目标是发现和开发抗艾滋病毒候选药物使用蓝藻技术。为了实现这一目标，该项目的目标是：1：构建并描述一个cyanobactin库。2：从文库中制备并纯化15000 ~ 20000个蓝藻菌素，用于高通量筛选。3：使用基于细胞的检测方法从库中筛选15,000至20,000个蓝藻素用于抗hiv先导物，并确定10个“最适合”的先导物适合在II期进一步开发。

DESCRIPTION (provided by applicant): Natural products are still the majority of therapeutic agents. However, they suffer from a difficulty in the creation of derivatives, and they can also be hard to supply. Derivatives are extremely important in the optimization of properties, such as toxicity or solubility, that are critical to development of therapeutics. Recently, it has become increasingly popular to create libraries of derivatives using genetic engineering of natural product biosynthetic genes. Even in the best libraries, the numbers of derivatives are in the hundreds or low thousands. Recently, we discovered an evolutionary pathway that could potentially be harvested to generate up to billions of derivatives. The compounds can be rapidly "evolved" to improve desired properties while minimizing unwanted effects. We have developed a system in which new activities can be pharmacologically optimized in a matter of days to weeks, exploring a huge diversity of unnatural natural products. In this project, we will develop this system to produce anti-HIV compounds for rapid development. The evolutionary feature of this proposal will allow leads to be rapidly optimized to overcome common problems in drug development. Our goal is to discover and develop anti-HIV candidate pharmaceuticals using cyanobactin technology. In pursuit of this goal, the project aims are to: 1: Construct and characterize a cyanobactin library. 2: Prepare and purify 15,000 to 20,000 cyanobactins from the library for use in high throughput screening. 3: Screen 15,000 to 20,000 cyanobactins from the library for anti-HIV leads using cell-based assays and identify the ten "most fit" leads suitable for further development in Phase II. PUBLIC HEALTH RELEVANCE: We will use innovative new technology to develop optimized anti-HIV agents with a variety of mechanisms. These agents will be leads for clinical development.