Dehydroamino Acids as Stabilizing and Rigidifying Components of Bioactive Peptides and Natural Products: Synthetic, Structural, and Medicinal Studies

脱氢氨基酸作为生物活性肽和天然产物的稳定和硬化成分：合成、结构和药物研究

• 批准号: 10046403
• 负责人: STEVEN L CASTLE
• 金额: $ 43.65万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046403
• 关键词: Acids; Amino Acids; Area; Biological; Biology; Cell Membrane Permeability; Chemicals; Collection; Complement; Dehydration; Development; Disease; Family; Goals; Health; Human; Knowledge; Malignant Neoplasms; Methodology; Methods; Mission; Modification; Molecular Conformation; Natural Products; Outcome; Peptide Hydrolases; Peptide Synthesis; Peptides; Perception; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plant Resins; Property; Public Health; Research; Role; Route; Solid; Structure; Sulfhydryl Compounds; Testing; Therapeutic; Therapeutic Agents; United States National Institutes of Health; Work; analog; anti-cancer; bioactive natural products; design; human disease; improved; innovation; peptide structure; physical property; promoter; protein protein interaction; stereochemistry; tool

Project Summary Dehydroamino acids (AAs) can increase the proteolytic stability of peptides as a result of a rigidifying effect caused by A1,3 strain that favors folded structures over random coil conformations. These residues should have great value to medicinal chemists and chemical biologists, but many types of AAs remain unexplored due to significant synthetic challenges. Accordingly, the objective of this proposal is to devise efficient routes to a range of AAs and then investigate the structures, stabilities, and potencies of peptides and natural products that contain them. The hypothesis is that new and efficient synthetic strategies will unlock access to a collection of AAs that can be used to tune the conformations, physical properties, and bioactivities of peptides. The rationale for this idea is that expanding the number of available AAs and defining their effects on peptide structure and function will provide new tools that will enable solutions to significant problems with relevance to human health. The hypothesis will be tested by pursuing three Specific Aims. Aim 1 involves expanding the realm of available ,-AAs and devising new methods of incorporating them into peptides. Cyclic AAs and fluorinated AAs will be targeted. The new methodologies will include dehydrations and related eliminations that can be conducted on a solid support and are compatible with solid-phase peptide synthesis (SPPS). Aim 2 entails determining the impact of various types of ,-AAs on peptide structure and stability as well as probing medicinal applications of peptides containing these residues. Secondary structures to be studied include turns, sheets, and helices. The inclusion of ,-AAs in anticancer peptides and -sheet breaker peptides will be explored. Aim 3 consists of devising a robust synthesis of AAs containing the -thioenamide moiety and using it as part of an effort to determine the stereochemistry of the thioviridamide macrocycle. The thioviridamides are potent and selective anticancer peptides that contain the AA aminovinylcysteine. This residue will be constructed using an oxidative decarboxylative elimination that will be employed to construct 16 candidate structures of the thioviridamide macrocycle using SPPS. The approach is innovative because it upends the conventional wisdom stating that AAs are poorly suited to incorporation into bioactive peptides due to the perception that they are reactive to biological nucleophiles such as thiols. The significance of the proposed research lies in its ability to facilitate the use of peptides that contain AAs to solve important medicinal chemistry and chemical biology problems. Such studies could include the design of proteolytically stable peptides that are capable of disrupting protein–protein interactions with relevance to human diseases or the development of potent and stable analogs of the thioviridamides. This project is envisioned to raise the profile of AAs, which have been previously underutilized.

项目概要 脱氢氨基酸 (AA) 可以通过刚性化作用提高肽的蛋白水解稳定性 由 A1,3 应变引起，该应变有利于折叠结构而不是随机卷曲构象。这些残基应该具有。 对于药物化学家和化学生物学家来说具有巨大价值，但由于以下原因，许多类型的 AA 仍未被探索 因此，该提案的目标是设计通往一系列的有效路线。 AA，然后研究肽和天然产物的结构、稳定性和效力， 假设新的、有效的合成策略将解锁对一组数据的访问。 AA 可用于调节肽的构象、物理性质和生物活性。 这个想法是扩大可用的 AA 的数量并定义它们对肽结构和 功能将提供新的工具，能够解决与人类健康相关的重大问题。 该假设将通过追求三个具体目标来检验，目标 1 涉及扩大可用领域。 ,-AA 并设计将它们掺入肽中的新方法。 新方法将包括可进行的脱水和相关消除。 目标 2 需要确定固相肽合成 (SPPS)。 各种类型的α,β-αAA对肽结构和稳定性的影响以及探索医学应用 含有这些残基的肽的二级结构包括转角、折叠和螺旋。 目标 3 将探讨在抗癌肽和 β-折叠肽中添加 α,β-αAA。 设计一种包含 -硫烯酰胺部分的 AA 的稳健合成方法，并将其作为努力的一部分 确定硫代病毒酰胺大环的立体化学 硫代病毒酰胺是有效的和选择性的。 含有 AA 氨基乙烯基半胱氨酸的抗癌肽将使用氧化酶构建。 脱羧消除将用于构建 thioviridamide 的 16 个候选结构 使用 SPPS 的大循环方法是创新的，因为它颠覆了传统观点： AA 不太适合掺入生物活性肽，因为人们认为它们对 生物亲核试剂，例如硫醇，这项研究的意义在于它能够促进 使用含有 AA 的肽来解决重要的药物化学和化学生物学问题。 研究可能包括设计能够破坏蛋白质-蛋白质的蛋白水解稳定肽 与人类疾病相关的相互作用或有效且稳定的类似物的开发 该项目旨在提高此前未得到充分利用的 AA 的知名度。