Development and characterization of heterocyclized dipeptide derivatives as inhibitors for heterotrimeric G proteins

作为异三聚体 G 蛋白抑制剂的杂环化二肽衍生物的开发和表征

• 批准号: 290875114
• 负责人: Professor Dr. Michael Gütschow
• 金额: --
• 依托单位: Pharmazeutische und Medizinische Chemie
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290875114?language=en
• 关键词: Development; characterization; heterocyclized; dipeptide; derivatives

Heterotrimeric G proteins act as molecular switches and transduce extracellular signals via G protein-coupled receptors into intracellular signal cascades. This part of the project is aimed at developing focused libraries of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazines as Ga protein subfamily selective probes. Such probes would be highly desired to understand the detailed contribution of G protein signaling under physiological and pathophysiological conditions. The design of the tool compounds is based on the structures of two low-molecular weight, cell-permeable BIM molecules. These are considered as heterocyclized dipeptide derivatives, accessible for manifold structural modifications via combinatorial chemistry. It should be investigated to what extent the selectivity and suitability of the compounds can be improved in the course of a stepwise optimization. The new compounds will be provided to the collaborators of the consortium for biochemical and pharmacological evaluation and utilization.

异三聚体 G 蛋白充当分子开关，通过 G 蛋白偶联受体将细胞外信号转导为细胞内信号级联。该项目的这一部分旨在开发 5,6,7,8-四氢咪唑并[1,2-a]吡嗪的重点文库作为 Ga 蛋白亚家族选择性探针。非常需要此类探针来了解 G 蛋白信号传导在生理和病理生理条件下的详细贡献。工具化合物的设计基于两种低分子量、细胞可渗透的 BIM 分子的结构。这些被认为是杂环化二肽衍生物，可通过组合化学进行多种结构修饰。应该研究在逐步优化的过程中化合物的选择性和适用性可以提高到什么程度。新化合物将提供给该联盟的合作者进行生化和药理评价和利用。

项目成果

Bioanalytical verification of V-type nerve agent exposure: simultaneous detection of phosphonylated tyrosines and cysteine-containing disulfide-adducts derived from human albumin

• DOI: 10.1007/s00216-017-0787-7
• 发表时间: 2018-02-01
• 期刊: ANALYTICAL AND BIOANALYTICAL CHEMISTRY
• 影响因子: 4.3
• 作者: Kranawetvogl, Andreas;Kueppers, Jim;John, Harald
• 通讯作者: John, Harald

Transformation of the Carboxyl Group of an Amino Acid to Variously Substituted Imidazoles through a Davidson-Type Heterocyclization

通过戴维森型杂环化将氨基酸的羧基转化为各种取代的咪唑

• DOI: 10.1055/s-0037-1612084
• 发表时间: 1961
• 期刊: Synthesis
• 作者: Küppers;Hympánová;Keuler;Schneider;Schnakenburg G;Gütschow
• 通讯作者: Gütschow

Label-Free Whole Cell Biosensing for High-Throughput Discovery of Activators and Inhibitors Targeting G Protein-Activated Inwardly Rectifying Potassium Channels

• DOI: 10.1021/acsomega.8b02254
• 发表时间: 2018-11-01
• 期刊: ACS OMEGA
• 影响因子: 4.1
• 作者: Krebs, Katrin M.;Pfeil, Eva M.;Kostenis, Evi
• 通讯作者: Kostenis, Evi

Crosstalk between angiotensin and the nonamyloidogenic pathway of Alzheimer's amyloid precursor protein

• DOI: 10.1111/febs.14015
• 发表时间: 2017-03-01
• 期刊: FEBS JOURNAL
• 影响因子: 5.4
• 作者: Kanarek, Anna Maria;Wagner, Annika;Kojro, Elzbieta
• 通讯作者: Kojro, Elzbieta