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.

说明(申请人提供)：天然产品仍然是治疗药物的主要成分。然而，它们在创造衍生品方面遇到了困难，而且它们也可能很难供应。衍生物在优化性质方面非常重要，例如毒性或溶解性，而这些性质对治疗学的发展至关重要。最近，利用天然产物生物合成基因的基因工程建立衍生物库已经变得越来越流行。即使在最好的图书馆里，衍生词的数量也只有数百或更少的数千。最近，我们发现了一条进化路径，有可能被收获以产生高达数十亿美元的衍生品。这些化合物可以快速“进化”，以改善所需的性能，同时将有害的影响降至最低。我们已经开发了一个系统，在这个系统中，新的活动可以在几天到几周的时间内进行药理优化，探索各种非天然天然产品。在这个项目中，我们将开发这一系统，以生产快速发展的抗艾滋病毒化合物。这一提议的进化特征将使Leads能够迅速优化，以克服药物开发中的常见问题。我们的目标是利用氰基丁酸技术发现和开发抗HIV候选药物。为了实现这一目标，该项目的目标是：1：构建并鉴定氰基丁酸菌素文库。2：从文库中制备和纯化15,000-20,000个氰基结合蛋白，用于高通量筛选。3：使用基于细胞的分析从库中筛选15,000到20,000个氰基结合蛋白以寻找抗艾滋病毒的引线，并确定适合在第二阶段进一步开发的10个“最适合”的引线。 公共卫生相关性：我们将利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领头羊。