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

7.项目摘要 药物设计的过程目前开始于药物先导和/或靶标。它涉及到铅的精炼 和靶向组合以实现高功效和降低脱靶效应的最佳特异性。的 拟议的探索性技术开发计划的重点是发现一个新的药物平台， 同时识别潜在客户和目标的设计。它结合了最近出现的“蛋白质模板 片段连接（PTFL）的概念与未充分探索的Paal-Knorr化学。为了技术的目的 在发展过程中，我们将努力集中在识别疼痛的新线索和目标上。该模型 为技术发展提供了一个理想的竞技场，因为美国的阿片类药物滥用已经达到 流行的比例，而目标建立的蛋白质，如考克斯-2已达到阈值， 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反应来递送新的考克斯-2，证明了所提出的平台的用途 含有吡咯的探针、命中物和引导物。由于许多靶标不能在体外表达和使用，因此我们将 专注于将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测目标的探针。虽然是为了发现新的 疼痛的线索，所提出的方法是一般性的，可以应用于治疗发现的一个 广泛的疾病，包括但不限于癌症、神经退行性疾病、中风和传染病 疾病如果成功的话，这项技术及其扩展可能会为下一代工具添加一个重要的功能， 进一步革新药物发现过程。

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.