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.

项目摘要/摘要 G蛋白偶联受体（GPCR）是用于药物发现的古老靶标。所有药物的三分之一 临床用途目标gpcr。许多GPCR的内源配体是肽，使肽理想 探索探索这些GPCR的结构活性关系的探针，以及开发调节的药物 他们的活动。虽然有几个本机GPCR肽配体已成功地转化为人类 疗法，绝大多数PK/PD特性困扰着毒品不足。更换 具有非蛋白酶氨基酸（NPAA）的肽中天然氨基酸（AAS）可以增强药物 - 像普通肽的特性一样，从而改善了它们作为药物的实际用途。所有GPCR肽的80％ 药物含有NPAA。确定要在肽中包含哪种NPAA以及将其放置在哪里 取决于反复试验，将每个肽变体作为单独的多步固体的独特产物做出 相位化学合成程序依赖于有限的NPAA池，固相耦合较差 效率。新技术使NPAA可以在一般的，合成的肽中引入肽 发散且具有成本效益的方式将（1）大大改善GPCR肽药物的开发 今天练习，（2）使访问全面的肽库彻底探索结构活动 GPCR的关系，以及（3）促进新合成方法的发展和部署，这将 反过来，合成化学和药物肽化学的领域。 我们的实验室开发了一种新的并行合成方法，该方法生成了整个库 单个步骤中的单个肽类似物。我们已经表明，该策略可以产生肽的库 其中，单个氨基酸转化为无数新的NPAA变体之一。进一步发展我们的 策略作为药物化学的一般工具，并证明了其优化GPCR肽的优势 我们在这里建议生成和评估我们实验室设计的新的GPCR肽配体的库 具有有希望的抗HIV活性。通过同时追求化学和生物学，我们将使用我们的新肽 作为完善和改善我们新铸造的化学方法的工具，准备（1）多个肽 NPAA和（2）含有D-氨基酸的肽，这将使我们的肽作为全新 抗逆转录病毒药物，将使我们的合成平台对GPCR肽药物的开发更有用。