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.

项目摘要 由于刚化作用，脱氢氨基酸（AA）可以提高肽的蛋白水解稳定性 由A1,3菌株引起的，该菌株有利于折叠结构而不是随机线圈构象。这些残留物应该有 对药物化学家和化学生物学家的巨大价值，但由于 巨大的合成挑战。彼此之间，该提案的目的是将高效的路线设计到一个范围 aas，然后研究宠物和天然产品的结构，系统和电位 包含它们。假设是，新的和高效的合成策略将解锁访问 可以用来调整肽的构象，物理特性和生物活性的AA。理由 对于这个想法是，扩大可用AA的数量并定义其对肽结构和 功能将提供新的工具，以使解决与人类健康相关的重大问题的解决方案。 该假设将通过追求三个具体目标来检验。 AIM 1涉及扩展可用的领域 ，-AA，并设计了将它们纳入肽的新方法。循环aas和氟化aas将会 是针对性的。新方法将包括可以进行的脱水和相关消除 在固体支持下，与固相肽合成（SPP）兼容。目标2实体确定 各种类型的，-AAS对肽结构和稳定性以及探测药物应用的影响 包含这些残差的肽。要研究的二级结构包括转弯，床单和螺旋。 将探索将，-aas纳入抗癌器petides和地面断裂器宠物中。 AIM 3组成 设计含有-硫酰胺部分的强大合成AA，并将其用作努力的一部分 确定硫代二胺大环的立体化学。硫代夫妇胺潜力和选择性 含有AA氨基甲甲基半胱氨酸的抗癌肽。该住宅将使用氧化构建 将进行脱羧的消除，以构建硫哥里二酰胺的16个候选结构 使用SPPS的大环。这种方法具有创新性，因为它颠覆了传统的智慧，说明 由于认为它们对生物活性辣椒的掺入，因此由于认为它们是反应性的，因此不适合将其掺入生物活性辣椒中 生物性核致化石，例如硫醇。拟议研究的意义在于它促进 使用含有AA的肽来解决重要的医学化学和化学生物学问题。这样的 研究可能包括能够破坏蛋白质 - 蛋白质的蛋白水解稳定的辣椒的设计 与与人类疾病相关的相互作用或潜力和稳定类似物的发展 硫代依他胺。设想该项目提高了以前未被充分利用的aas的概况。