New catalytic strategies to make non-proteinogenic peptides

项目摘要/摘要 G蛋白偶联受体(GPCRs)是药物发现的重要靶点。世界上三分之一的毒品 临床应用靶点为GPCRa。许多gpcr的内源性配体是多肽，这使得多肽成为理想的多肽。 探索这些GPCRs的构效关系，开发调节GPCRs的药物 他们的活动。虽然精选的几个天然GPCR多肽配体已经成功地翻译成人类 在治疗方面，绝大多数都受到PK/PD特性不足的困扰，药物非常糟糕。替换 多肽中的天然氨基酸(AAs)和非蛋白生成氨基酸(NPAAs)可增强药物的稳定性。 与普通多肽的性质相似，从而提高了其作为药物的实际用途。80%的gpr多肽 药物中含有NPAA。确定在多肽中包括哪些NPAA以及将它们主要放置在哪里 取决于试验和错误，每个多肽变体都是单独的多步固体的独特产物- 相化学合成过程，依赖于固相耦合较差的有限的NPAA池 效率。使NPAA能够被普遍地、合成地引入多肽的新技术 不同的、成本效益高的方式将(1)显著改善GPCR多肽药物的开发现状 今天的做法，(2)使访问全面的多肽文库，以彻底探索结构活性 GPCRs的关系，以及(3)促进开发和部署新的合成方法，这将 进而推动合成化学和药用多肽化学领域的发展。 我们的实验室开发了一种新的并行合成方法，它可以生成整个文库 一步完成单个多肽类似物的分离。我们已经证明，这种策略可以产生多肽文库。 其中一种氨基酸被转化为无数新的NPAA变体之一。为了进一步发展我们的 策略作为药物化学的通用工具，并展示其在优化GPCR肽方面的优势 我们建议在这里生成并评估我们实验室设计的一种新的GPCR肽配基的文库 具有良好的抗艾滋病毒活性。通过同时研究化学和生物，我们将使用我们的新肽 作为改进和改进我们最新化学方法学的载体，以制备(1)具有多个 NPAAs，以及(2)含有D-氨基酸的多肽，这将使我们的多肽成为一种全新的 抗逆转录病毒药物，并将使我们的合成平台更适用于GPCR多肽药物的开发。

PROJECT SUMMARY/ABSTRACT G protein-coupled receptors (GPCRs) are venerable targets for drug discovery. One-third of all drugs in clinical use target a GPCR. The endogenous ligands for many GPCRs are peptides, which make peptides ideal probes for exploring the structure-activity relationship of these GPCRs, and for developing drugs that modulate their activity. While a select few native GPCR peptide ligands have been successfully translated into human therapies, the vast majority are plagued by inadequate PK/PD properties and make very poor drugs. Replacing the natural amino acids (AAs) in the peptide with non-proteinogenic amino acids (NPAAs) can enhance the drug- like properties of ordinary peptides, thereby improving their practical use as medicines. 80% of all GPCR peptide drugs contain NPAAs. Determining which NPAAs to include in the peptide and where to place them largely depends on trial and error, each peptide variant being made as the unique product of a separate multi-step solid- phase chemical synthesis procedure that relies on a limited pool of NPAAs with poor solid-phase coupling efficiencies. New technologies which enable NPAAs to be introduced into peptides in a general, synthetically divergent, and cost-effective manner would (1) considerably improve GPCR peptide drug development as it is practiced today, (2) enable access to comprehensive peptide libraries to thoroughly explore structure-activity relationships of GPCRs, and (3) promote the development and deployment of new synthetic methods, which will in turn advance the fields of synthetic chemistry and medicinal peptide chemistry. Our laboratory has developed a new parallel synthesis approach that generates entire libraries of individual peptide analogs in a single step. We have shown that this strategy can yield libraries of peptides wherein a single amino acid is transformed to one of a myriad of new NPAA variants. To further develop our strategy as a general tool for medicinal chemistry and demonstrate its advantages for optimizing GPCR peptides we propose here to generate and to evaluate libraries of a new GPCR peptide ligand designed by our lab that has promising anti-HIV activity. By pursuing both chemistry and biology in parallel we will use our new peptide as a vehicle to refine and improve our newly minted chemical methodology to prepare (1) peptides with multiple NPAAs, and (2) peptides containing D-amino acids, which will advance our peptide as an entirely new antiretroviral drug and will make our synthetic platform more useful for GPCR peptide drug development.