New Reactions for Direct, Native Peptide Ligations

目的：提出的研究目标是开发一种全面的直接耦合方法。 通过一种新的化学选择性酰胺化反应获得无保护分子。这个项目的基础是 α-酮酸和A/-烷基羟胺的无试剂反应，通过脱羧基和烷基羟胺生成酰胺。 脱水。这些研究将为合成生物分子靶标提供新的方法，包括 蛋白质、糖肽和多肽模拟物。 具体目标： (1)研究酮酸羟胺(KAMA)的底物范围、局限性及作用机理 在不同的氨基酸对、反应条件和片段上连接和探索多肽连接 大小。进一步的努力将把这一过程应用于合成大肽的新方法。 (2)为实际合成含有必需官能团的片段提供新的化学方法。 C-端α-酮酸和/V-端羟胺。酮酸的制备方法如下： 基于一种新的固相连接物的温和的两步法。用于羟胺的合成， 易于引入合成的单体的实用制备方法 将确定多肽或碳水化合物。 (3)发展了一种无需偶联剂或偶联剂的多肽迭代合成新方法 保护团体。这种合成多肽的独特方法将通过合成 适用于合成新的多肽类药物的新单体。一个合适的实体的设计 支持将使这一过程能够直接应用于具有生物学意义的较长的多Y-肽。 意义重大。该研究将为直接合成酰胺提供一种新的化学工具。 在生理上相容的反应条件下。这将对络合物的合成产生重大影响。 生物分子包括蛋白质、糖蛋白、多肽模拟物和生物相容材料。

Objective: The goal of the proposed research is to develop a comprehensive method for the direct coupling of unprotected molecules via a new chemoselective amidation reaction. The basis for this project is the reagent-less reaction of a-ketoacids and A/-alkylhydroxylamines to give amides via decarboxylation and dehydration. These studies will provide new methods for the synthesis of biomolecule targets including proteins, glycopeptides, and peptidomimetics. Specific Aims: (1) To investigate the substrate scope, limitations, and mechanism of the ketoacid-hydroxylamine (KAMA) ligation and explore peptide ligations at various amino acid pairs, reaction conditions, and fragment sizes. Further efforts will apply this process to new approaches for the synthesis of large peptides. (2) To advance new chemistries for the practical synthesis of fragments containing the requisite functional groups, namely C-terminal a-ketoacids and /V-terminal hydroxylamines. The ketoacids are prepared by a mild two step protocol based on a new solid phase linker. For the synthesis of hydroxylamines, practical approaches to the preparation of monomers that can be easily introduced into a synthetic peptide or carbohydrate will be identified. (3) To develop a new approach to the iterative synthesis of poly-/?-peptides without coupling reagents or protecting groups. This unique approach to polypeptide synthesis will be expanded by synthesizing new monomers suitable for the synthesis of new peptidomimetics. The design of a suitable solid support will enable direct application of this process to longer poly-yS-peptides of biological significance. Significance. The proposed research will provide a new chemical tool for the direct synthesis of amides under physiologically compatible reaction conditions. It will significantly impact the synthesis of complex biomolecules including proteins, glycoproteins, peptidomimetics, and biocompatible materials.