Tandem Discovery of Drug Leads and Targets via Paal-Knorr reaction

通过 Paal-Knorr 反应串联发现先导药物和靶标

• 批准号: 10004127
• 负责人: ALEXANDER KORNIENKO
• 金额: $ 16.21万
• 依托单位: TEXAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004127
• 关键词: Alder plant; Amides; Amines; Binding; Biological Assay; Biology; Cell Survival; Cells; Chemicals; Chemistry; Chromatography; Communicable Diseases; Coupled; Development; Disease; Drug Design; Drug Targeting; Epidemic; Fluorescence Anisotropy; Fluorescent Probes; Goals; In Vitro; Lead; Ligands; Ligation; Malignant Neoplasms; Mammalian Cell; Methods; Microscopy; Modeling; Nature; Neurodegenerative Disorders; Nociception; PTGS2 gene; Pain; Pharmaceutical Preparations; Pharmacology; Physical condensation; Play; Process; Program Development; Proteins; Publishing; Pyrroles; Reaction; Recombinant Proteins; Role; Series; Specificity; Stroke; Structure-Activity Relationship; Techniques; Technology; Therapeutic; Translating; Translation Process; Translations; United States; United States National Institutes of Health; Validation; base; chemical reaction; cycloaddition; cyclooxygenase 2; design; diketone; drug discovery; guided inquiry; high reward; high risk; improved; next generation; novel; opioid misuse; programs; screening; small molecule; technology development; tool

7. Project Summary The process of drug design currently begins with a drug lead and/or target. It involves the refinement of that lead and target combination to achieve optimal specificity for high efficacy and reduced off-target effects. The proposed exploratory technology development program focuses on the discovery of a new platform for drug design that identifies both lead and target in parallel. It combines the recently emerged ‘protein-templated fragment ligation (PTFL)’ concept with underexplored Paal-Knorr chemistry. For the purpose of technology development, we have centered our efforts on the identification of new leads and targets for pain. This model provides an ideal arena for technology development since opioid misuse in the United States has attained epidemic proportions while targeting established proteins such as COX-2 has reached a threshold generating an emergent need to rapidly discover and explore alternative targets. As the first Specific Aim, we will demonstrate the use of the proposed platform by employing the Paal-Knorr reaction to deliver novel COX-2 pyrrole-containing probes, hits and leads. As many targets cannot be expressed and used in vitro, we will then focus on translating the platform to operate in mammalian cells. As the second Specific Aim, we will demonstrate how our method can be used to identify probes to unexplored targets. While developed for the discovery of new leads for pain, the proposed approach is general in nature and can be applied for therapeutic discovery for a wide range of ailments including but not limited to cancer, neurodegenerative diseases, stroke, and infectious disease. If successful, this technology and expansions thereon could add an important next-generation tool to further revolutionize the drug discovery process.

7。项目摘要 目前，药物设计的过程始于药​​物铅和/或靶标。它涉及该铅的完善 和目标组合，以实现高效率和降低目标效应的最佳特异性。这 拟议的探索技术开发计划的重点是发现新的药物平台 设计可以并行识别铅和目标。它结合了最近出现的“蛋白质” 碎片连接（PTFL）的概念，具有未充满底的PAAL-KNORR化学。为了技术的目的 开发，我们将努力集中在识别新潜在客户和疼痛目标上。这个模型 自从美国参加阿片类药物以来，为技术开发提供了理想的舞台 靶向建立的蛋白质（例如COX-2）的流行比例已达到阈值 紧急需要迅速发现和探索替代目标。作为第一个特定目标，我们将 通过使用PAAL-KNORR反应提供新的COX-2，证明了提出的平台的使用 含吡咯的问题，命中和潜在客户。由于无法在体外表达和使用许多目标，因此我们将 专注于将平台转换为在哺乳动物细胞中操作。作为第二个特定目标，我们将证明 如何使用我们的方法来识别出意外目标的问题。虽然开发了新的 疼痛的铅，提出的方法本质上是一般的，可以用于治疗发现 广泛的疾病包括但不限于癌症，神经退行性疾病，中风和传染性 疾病。如果成功的话，此技术和扩展可能会添加一个重要的下一代工具 进一步彻底改变了药物发现过程。