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.

项目总结/摘要 G蛋白偶联受体（GPCR）是药物发现的古老靶点。三分之一的毒品 临床使用靶向GPCR。许多GPCR的内源性配体是肽，这使得肽成为理想的配体。 探针用于探索这些GPCR的结构-活性关系，并用于开发调节 他们的活动。虽然选择的少数天然GPCR肽配体已经成功地翻译到人类中， 在治疗中，绝大多数都受到PK/PD特性不足的困扰，并且使药物非常差。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- 类似于普通肽的性质，从而改善其作为药物的实际用途。所有GPCR肽的80% 药物含有NPAAs。确定肽中包含哪些NPAA以及将其主要放置在何处 依赖于反复试验，每种肽变体都是作为单独的多步骤固体的独特产物制备的- 相化学合成方法，该方法依赖于有限的固相偶联较差的NPAA库 效率。新技术使NPAA能够以一般的合成方式引入肽中， 发散的，成本有效的方式将（1）大大改善GPCR肽药物的开发，因为它是 今天实践，（2）能够访问全面的肽库，以彻底探索结构-活性 GPCR的关系，以及（3）促进新的合成方法的开发和部署，这将 进而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 单个肽类似物在单个步骤中。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。更进一步拓展我们 策略作为药物化学通用工具，并展示其优化GPCR肽的优势 我们在此提出生成并评估由我们实验室设计的新GPCR肽配体的文库， 具有良好的抗HIV活性。通过同时研究化学和生物学，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载体，以制备（1）具有多个 NPAAs，和（2）含有D-氨基酸的肽，这将推动我们的肽作为一个全新的 这将使我们的合成平台对GPCR肽药物开发更有用。