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(-AAs)由于具有刚性作用，可以增加多肽的蛋白水解性 由A1，3菌株引起的，这种菌株更倾向于折叠结构而不是随机卷曲构象。这些残留物应该有 对药物化学家和化学生物学家来说很有价值，但由于以下原因，许多类型的AA仍未被开发 重大的合成挑战。因此，这项提议的目标是设计有效的路线到达某一范围 然后研究多肽和天然产物的结构、稳定性和效力，这些多肽和天然产物是AAs的 遏制他们。假设是，新的和有效的合成策略将打开对一系列 氨基酸，可用于调节多肽的构象、物理性质和生物活性。其基本原理是 因为这个想法是，扩大可用的AA的数量，并定义它们对肽结构和 这一功能将提供新的工具，使解决与人类健康相关的重大问题成为可能。 这一假设将通过追求三个具体目标来检验。目标1涉及扩大可用的范围 ，-氨基酸，并设计将它们结合到多肽中的新方法。环状AA和氟化AA将 成为靶子。新的方法将包括脱水和可以进行的相关消除 并与固相多肽合成(SPPS)兼容。目标2需要确定 不同类型，-氨基酸对多肽结构和稳定性的影响及其药用价值探讨 含有这些残基的多肽。要研究的二级结构包括转弯、片状和螺旋。 将探索，-氨基酸在抗癌多肽和-折叠破碎肽中的包含性。目标3包括 设计了一种含有-硫代酰胺部分的AA的强健合成，并将其用作努力的一部分 确定硫代维达胺大环的立体化学。硫代病毒胺是有效的和选择性的。 含有AA氨基半胱氨酸的抗癌肽。该残基将使用氧化剂构建 将被用于构建16个硫代病毒胺候选结构的脱羧基消除 使用SPPS的大循环。这种方法是创新的，因为它颠覆了传统的观点，即 氨基酸不太适合加入到生物活性多肽中，因为人们认为它们对 生物亲核剂，如硫醇。拟议研究的意义在于它能够促进 使用含有氨基酸的多肽来解决重要的药物化学和化学生物学问题。是这样的 研究可能包括设计能够破坏蛋白质-蛋白质的蛋白质分解稳定的多肽。 与人类疾病相关的相互作用或开发有效和稳定的类似物 硫代病毒胺。该项目旨在提高以前未得到充分利用的AA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.