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

项目摘要 脱氢氨基酸（Dehydroamino acids，DEAAs）作为硬化作用的结果可以增加肽的蛋白水解稳定性 由A1，3应变引起，其有利于折叠结构而不是无规卷曲构象。这些残留物应该 这对药物化学家和化学生物学家来说具有很大的价值，但由于 重大的合成挑战。因此，本建议的目的是设计有效的路线， 然后研究肽和天然产物的结构，稳定性和效力， 遏制他们。假设是，新的和有效的合成策略将解锁一系列 可用于调节肽的构象、物理性质和生物活性的氨基酸。的理由 因为这个想法是，扩大可用的BTAAs的数量，并确定它们对肽结构的影响， 该功能将提供新的工具，能够解决与人类健康有关的重大问题。 将通过追求三个具体目标来检验假设。目标1涉及扩展可用的领域 并设计将它们掺入肽中的新方法。环状的二氨基三乙酸和氟化的二氨基三乙酸将 成为目标。新的方法将包括脱水和相关的消除， 在固体支持物上，并且与固相肽合成（SPPS）相容。目标2需要确定 不同类型的α，β-β-AA对肽结构和稳定性的影响以及探索药物应用 含有这些残基的肽。要研究的二级结构包括转角、片层和螺旋。 将探索在抗癌肽和β-折叠破坏肽中包含β-、β-、β-AA。目标3包括 设计了一种含有β-硫代烯酰胺部分的β-AAAs的稳健合成，并将其用作努力的一部分， 确定硫代病毒胺大环的立体化学。硫代病毒酰胺是有效的和选择性的 抗癌肽，含有氨基乙烯基半胱氨酸。该残留物将使用氧化的 脱羧消除，将用于构建硫代病毒胺的16个候选结构 使用SPPS的大循环。这种方法是创新的，因为它颠覆了传统智慧， 由于认为它们对生物活性肽具有反应性，所以BCAA不太适合掺入生物活性肽中。 生物亲核试剂如硫醇。拟议研究的意义在于它能够促进 使用含有BTAAs的肽来解决重要的药物化学和化学生物学问题。等 研究可以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开发有效和稳定的类似物， thioviridamides。预计该项目将提高以前利用不足的联合国海洋事务和海洋法署的知名度。

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.