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

发现用于治疗和预防 HIV 感染的药物

• 批准号: 7932473
• 负责人: Robert Walter Buckheit
• 金额: $ 26.83万
• 依托单位: SYMBION DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932473
• 关键词: Anti-HIV Agents; Anti-Infective Agents; Biological Assay; Biological Factors; Cells; Clinical; Development; Drug usage; Engineering; Escherichia coli; Family; Funding; Genes; Genetic Engineering; Goals; HIV Infections; HIV therapy; Harvest; Human; Lead; Libraries; Molecular; Natural Products Chemistry; Pathway interactions; Peptide Library; Peptides; Phage Display; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Point Mutation; Prevention; Process; Property; Research; Small Business Innovation Research Grant; Solubility; Speed; System; Technology; Therapeutic; Therapeutic Agents; Toxic effect; base; drug development; drug discovery; experience; high throughput screening; improved; innovation; member; new technology; public health relevance; small molecule; therapeutic development

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.

描述（由申请人提供）：天然产品仍然是大多数治疗剂。但是，它们在创建衍生物方面遇到了困难，而且也很难提供。衍生物在优化对疗法发展至关重要的毒性或溶解性等性质中极为重要。最近，使用天然产物生物合成基因的基因工程创建衍生物库越来越流行。即使在最好的库中，衍生物的数量也在数百或低位。 最近，我们发现了一种进化途径，该途径有可能收获以产生多达数十亿个衍生物。这些化合物可以迅速“进化”以改善所需的特性，同时最大程度地减少不良影响。我们已经开发了一个系统，可以在几天到几周内在药理学上优化新活动，从而探索大量不自然的天然产品。在这个项目中，我们将开发该系统以生产抗HIV化合物以进行快速开发。该提案的进化特征将允许迅速优化铅，以克服药物开发中的常见问题。 我们的目标是使用氰基甲分激素技术发现和开发抗HIV候选药物。为了实现这一目标，该项目的目的是：1：构建和描述氰基乳酸图书馆。 2：从图书馆中准备并净化15,000至20,000氰基素，以在高吞吐量筛选中使用。 3：使用基于细胞的测定法，屏幕上的15,000至20,000只氰基素，用于抗HIV引线，并确定适合于II期进一步发展的十个“最合适”导线。 公共卫生相关性：我们将使用创新的新技术来开发具有多种机制的优化反HIV代理。这些药物将成为临床开发的铅。