Synthesis and characterization of macrocyclic peptide inhibitors of the Galpha protein family

Gα蛋白家族大环肽抑制剂的合成和表征

• 批准号: 290832253
• 负责人: Professorin Dr. Diana Imhof, Ph.D.
• 金额: --
• 依托单位: Department of Chemistry and Biochemistry
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290832253?language=en
• 关键词: Synthesis; characterization; macrocyclic; peptide; inhibitors

Molecules that interfere with the activity of heterotrimeric G proteins represent valuable tools for a better understanding of the protein structure and its mechanism of action. Such compounds, in addition, may also turn out suitable substances for investigating physiological states and may thus provide insight into the respective mechanisms. The clear demand for specific G protein inhibitors has not been satisfied yet. Thus, it is the primary aim of this project to design and synthesize macrocyclic peptide inhibitors with improved physico-chemical and pharmacological properties. The investigations are based on the existing cyclic depsipeptide FR900359 and the structurally related YM-254890. Structurally simplified molecules will initially serve first as templates for a stepwise optimization of the reaction conditions for the synthesis of individual YM-related peptides. For this purpose, protocols for solid phase peptide synthesis will be established based on the introduction of building blocks and manuals for difficult sequences to cope with the structural demands of the natural counterpart. Methods for peptide purification and analytical characterization will serve as prerequisite to supply sufficient material for structure elucidation and biological testing. In turn, information from solution NMR analysis and different bioassays will be used to perform in-depth structure-activity relationship studies and computational design of specific G protein inhibitors. In a second approach, the search for such inhibitors of different Galpha proteins will be supported by screening a combinatorial peptide library, which will be constructed based on the initial investigations using building blocks. Evaluation of the compounds binding capacities and inhibitory properties as well as their structure-activity relationships will be additionally supported by the envisaged provision of recombinantly expressed G proteins. Altogether, these studies may provide important tools to offer a profound insight into the mechanism of action of individual G proteins and potential novel substances for studying physiological pathways involving G proteins.

干扰异源三聚体G蛋白活性的分子代表了更好地理解蛋白质结构及其作用机制的有价值的工具。此外，这些化合物还可以产生用于研究生理状态的合适物质，从而可以提供对相应机制的深入了解。对特异性G蛋白抑制剂的明确需求尚未得到满足。因此，本课题的主要目的是设计和合成具有更好的理化和药理性质的大环肽抑制剂。这些研究是基于现有的环状缩酚酸肽FR 900359和结构相关的YM-254890。结构简化的分子最初将首先作为模板，用于逐步优化合成单个YM相关肽的反应条件。为此，固相肽合成的方案将建立在引入结构单元和手册的基础上，以科普天然对应物的结构需求。肽纯化和分析表征方法将作为为结构解析和生物学测试提供足够材料的先决条件。反过来，来自溶液NMR分析和不同生物测定的信息将用于进行深入的结构-活性关系研究和特定G蛋白抑制剂的计算设计。在第二种方法中，将通过筛选组合肽文库来支持对不同Galpha蛋白质的此类抑制剂的搜索，所述组合肽文库将基于使用构件的初始研究来构建。化合物结合能力和抑制特性以及它们的结构-活性关系的评价将另外通过重组表达的G蛋白的设想提供来支持。总之，这些研究可能提供重要的工具，提供一个深刻的洞察个别G蛋白的作用机制和潜在的新物质，研究涉及G蛋白的生理途径。