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

描述（由申请人提供）：天然产品仍然是大多数治疗药物。然而，它们在创造衍生品方面遇到了困难，而且它们也很难供应。衍生物在优化性质（例如毒性或溶解度）方面极其重要，这对于开发治疗剂至关重要。最近，利用天然产物生物合成基因的基因工程来创建衍生物文库已经变得越来越流行。即使在最好的图书馆里，衍生品的数量也只有几百或几千个。 最近，我们发现了一种进化途径，可以被收获以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。我们开发了一个系统，可以在几天到几周的时间内对新活动进行优化，探索各种各样的非自然天然产品。在这个项目中，我们将开发这个系统来生产抗HIV化合物，以实现快速发展。该提案的进化特征将允许快速优化线索，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病毒的候选药物使用氰基菌素技术。为了实现这一目标，本项目的目标是：1：构建和表征氰氧化菌素文库。 2：从文库中制备并纯化15，000至20，000个蓝藻菌素，用于高通量筛选。 第三章：使用基于细胞的分析从库中筛选15，000到20，000个抗HIV先导化合物的蓝藻，并确定10个“最适合”的先导化合物，适合在第二阶段进一步开发。 公共卫生相关性：我们将使用创新的新技术开发具有多种机制的优化抗艾滋病毒药物。这些药物将成为临床开发的先导药物。

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.