New Reactions for Direct, Native Peptide Ligations

直接、天然肽连接的新反应

• 批准号: 7536201
• 负责人: Jeffrey William Bode
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536201
• 关键词: Aldehydes; Amides; Amino Acids; Biocompatible Materials; Biological; Buffers; C-terminal; Carbohydrates; Carbon Dioxide; Carboxylic Acids; Chemicals; Chemistry; Class; Compatible; Complex; Condition; Coupling; Decarboxylation; Dehydration; Development; Discipline; Glycopeptides; Glycoproteins; Goals; Hydroxylamine; Keto Acids; Ligation; Methodology; Methods; Modification; N-terminal; Object Attachment; Peptide Synthesis; Peptides; Phase; Preparation; Process; Property; Protein Engineering; Proteins; Protocols documentation; Range; Reaction; Reagent; Research; S Phase; Side; Site; Solid; Solvents; Structure; Sulfur; Variant; Water; Work; amidation; aqueous; base; catalyst; design; direct application; drug development; functional group; human disease; monomer; novel; novel strategies; novel therapeutics; peptidomimetics; polypeptide; size; success; synthetic peptide; tool; ylide

DESCRIPTION (provided by applicant): 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 alpha-ketoacids and N-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 alpha-ketoacids and N-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-beta-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-beta-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.

描述（由申请人提供）：目的：拟议的研究的目的是开发一种通过新的化学选择性障碍反应直接耦合未保护分子的综合方法。该项目的基础是α-酮酸和N-烷基羟胺的无试剂反应通过脱羧和脱水而产生酰胺。这些研究将为合成包括蛋白质，糖肽和肽仪的生物分子靶标合成新方法。具体目的：（1）研究酮酸 - 羟胺（KAMA）连接的底物范围，局限性和机制，并在各种氨基酸对，反应条件和碎片大小上探索肽连接。进一步的努力将把这一过程应用于合成大肽的新方法。 （2）推进新的化学物质，用于实际合成包含必要官能团的片段，即C末端α-酮酸和N末端羟胺。酮酸由基于新的固相连接器的温和两步协议制备。对于羟胺的合成，将确定可以轻松地引入合成肽或碳水化合物的单体制备的实际方法。 （3）开发一种新的方法来迭代合成多β肽，而无需偶联试剂或保护组。这种独特的多肽合成方法将通过合成适合合成新肽仪的新单体而扩展。合适的固体支持的设计将使该过程直接应用于具有生物学意义的更长的多β肽。意义。拟议的研究将为在生理兼容的反应条件下直接合成酰胺的新化学工具。它将显着影响复杂的生物分子的合成，包括蛋白质，糖蛋白，肽仪和生物相容性材料。