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）：天然产物仍然是大多数治疗剂。然而，它们在创造衍生品方面遇到困难，而且也很难供应。衍生物对于优化毒性或溶解度等特性极其重要，这些特性对于治疗药物的开发至关重要。最近，利用天然产物生物合成基因的基因工程创建衍生物文库变得越来越流行。即使在最好的图书馆中，衍生品的数量也只有数百或数千。 最近，我们发现了一条进化途径，有可能产生数十亿种衍生物。这些化合物可以快速“进化”以改善所需的特性，同时最大限度地减少不良影响。我们开发了一个系统，可以在几天到几周内对新活性进行药理学优化，探索多种非天然天然产品。在这个项目中，我们将开发这个系统来生产抗HIV化合物，以实现快速开发。该提案的进化特征将使先导化合物能够快速优化，以克服药物开发中的常见问题。 我们的目标是利用氰菌素技术发现和开发抗艾滋病毒候选药物。为了实现这一目标，该项目的目标是： 1：构建并表征蓝藻素库。 2：从文库中制备并纯化 15,000 至 20,000 个蓝菌素，用于高通量筛选。 图 3：使用基于细胞的测定从库中筛选 15,000 至 20,000 个蓝菌素，寻找抗 HIV 线索，并确定适合在 II 期进一步开发的 10 个“最合适”线索。 公共健康相关性：我们将利用创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。