New catalytic strategies to make non-proteinogenic peptides

制造非蛋白肽的新催化策略

• 批准号: 10501950
• 负责人: Steven Bloom
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501950
• 关键词: Amino Acids; Anti-Retroviral Agents; Biology; CXCR4 gene; Chemicals; Chemistry; Clinical; Coupling; Development; Drug Receptors; Drug Targeting; G-Protein-Coupled Receptors; GPR3 gene; GTP-Binding Protein alpha Subunits, Gs; Genus Mentha; HIV; Human; Individual; Laboratories; Libraries; Ligands; Medicine; Methodology; Methods; Peptide Library; Peptide Receptor; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Procedures; Property; Solid; Structure-Activity Relationship; Synthesis Chemistry; Time; Translating; Variant; chemical synthesis; cost effective; design; drug development; drug discovery; improved; new technology; next generation; novel; peptide analog; peptide drug; pharmacokinetics and pharmacodynamics; tool; unnatural amino acids

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.

项目概要/摘要 G 蛋白偶联受体 (GPCR) 是药物发现的重要靶标。三分之一的药物 临床使用以 GPCR 为目标。许多 GPCR 的内源配体是肽，这使得肽成为理想的选择 用于探索这些 GPCR 的结构-活性关系以及开发调节药物的探针 他们的活动。虽然一些精选的天然 GPCR 肽配体已成功转化为人类 治疗中，绝大多数都受到 PK/PD 特性不足的困扰，并且生产的药物质量非常差。更换 肽中的天然氨基酸（AAs）与非蛋白氨基酸（NPAAs）可以增强药物- 与普通肽类似的特性，从而改善其作为药物的实际用途。占所有 GPCR 肽的 80% 药物含有 NPAA。确定肽中包含哪些 NPAA 以及将它们主要放置在何处 取决于反复试验，每个肽变体都是作为单独的多步骤固体的独特产物而制成的 相化学合成程序依赖于有限的 NPAA 库，且固相耦合较差 效率。新技术使 NPAA 能够以通用、合成的方式引入肽中 不同且具有成本效益的方式将 (1) 显着改善 GPCR 肽药物的开发 今天实践的，(2) 能够访问全面的肽库以彻底探索结构-活性 GPCR 的关系，(3) 促进新合成方法的开发和部署，这将 反过来又推动了合成化学和药用肽化学领域的发展。 我们的实验室开发了一种新的并行合成方法，可以生成整个库 一步即可获得单个肽类似物。我们已经证明这种策略可以产生肽库 其中单个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优化 GPCR 肽的优势 我们在此建议生成并评估我们实验室设计的新 GPCR 肽配体库，该配体 具有良好的抗 HIV 活性。通过并行研究化学和生物学，我们将使用我们的新肽 作为改进和改进我们新发明的化学方法的工具，以制备 (1) 具有多种活性的肽 NPAA，以及 (2) 含有 D-氨基酸的肽，这将使我们的肽成为一种全新的肽 抗逆转录病毒药物，将使我们的合成平台更适用于 GPCR 肽药物的开发。