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.

七、项目概要 目前，药物设计过程从药物先导物和/或靶标开始。它涉及到该线索的细化 和靶标组合，以实现最佳特异性，从而实现高功效并减少脱靶效应。这 拟议的探索性技术开发计划侧重于发现新的药物平台 并行识别先导和目标的设计。它结合了最近出现的“蛋白质模板” 片段连接 (PTFL) 概念与尚未充分探索的 Paal-Knorr 化学。以科技为目的 在开发过程中，我们将工作重点放在确定疼痛的新线索和目标上。这个型号 由于阿片类药物在美国的滥用已经达到 流行病比例，同时针对 COX-2 等已建立的蛋白质已达到产生的阈值 迫切需要快速发现和探索替代目标。作为第一个具体目标，我们将 通过采用 Paal-Knorr 反应来展示新型 COX-2 的使用 含吡咯的探针、命中物和先导物。由于许多靶点无法在体外表达和使用，那么我们将 专注于将该平台转化为在哺乳动物细胞中运行。作为第二个具体目标，我们将展示 我们的方法如何用于识别未探索目标的探针。为发现新事物而开发 导致疼痛，所提出的方法本质上是通用的，可以应用于以下疾病的治疗发现： 多种疾病，包括但不限于癌症、神经退行性疾病、中风和传染病 疾病。如果成功，这项技术及其扩展可能会增加一个重要的下一代工具 进一步彻底改变药物发现过程。