Modulation of PDZ domain-mediated protein-protein interactions

PDZ 结构域介导的蛋白质-蛋白质相互作用的调节

• 批准号: 35756367
• 负责人: Professor Dr. Hartmut Oschkinat
• 金额: --
• 依托单位: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/35756367?language=en
• 关键词: Modulation; PDZ; domain; mediated; protein

PDZ (PSD-95, Dlg, ZO-1) domains play important roles in cellular signalling pathways by mediating protein-protein interactions. The native peptide ligands bind into a ridge between a ß-strand and the C-terminal helix which has properties of a small-molecule binding site. Inhibitors with low to medium affinity for several PDZ domains were identified in the first funding period and members of the respective substance classes were collected in a PDZ-library . Improvements of the AF6 PDZ domain Inhibitors by modelling-chemistry cycles resulted in compounds with ten to twenty micromolar dissociation constants, disrupting the AF6-Bcr interaction in cell lysates. In the second funding period we want to exploit our results and focus on three PDZ domains (AF6, DVL, Shank3), aiming at an understanding of the biology of the respective proteins. The AF6 PDZ domain inhibitors will be investigated further in cell biological and in vivo experiments using a zebra fish model (collaboration with Ted Allison, Alberta). Inhibitors of Dishevelled (DVL9) will be investigated with respect their effects on the Wnt signalling pathway in collaboration with TP 9 (Birchmeier, von Kries). The role of the Shank3 in the postsynaptic density will be investigated together with Dietmar Schmitz, of the Berlin Neurocure program. The identification of selectivity patterns of PDZ domains by computational methods will help to further develop even more specific inhibitors. Specific ligands will be generated by cycles of NMR-spectroscopic investigations, Computer assisted ligand design, and medicinal chemistry. As a model case we will develop specific ligands binding to CAL but not to NHERF, two proteins playing crucial roles in cystic fibrosis.

PDZ（PSD-95，DLG，ZO-1）结构域通过介导蛋白质 - 蛋白质相互作用在细胞信号通路中起重要作用。天然肽配体与具有小分子结合位点的特性的ß链和C末端螺旋之间结合。在第一个资金期间鉴定出对多个PDZ结构域的低至中等亲和力的抑制剂，并在PDZ-fibrary中收集了相应物质类别的成员。通过模块化化学周期改善AF6 PDZ结构域抑制剂，导致具有10至20个微摩尔解离常数的化合物，破坏了细胞裂解物中的AF6-BCR相互作用。在第二个资金期间，我们希望探索我们的结果，并专注于三个PDZ领域（AF6，DVL，Shank3），旨在了解各个蛋白质的生物学。将使用斑马鱼模型（与艾伯塔省Ted Allison的合作）在细胞自由主义和体内实验中进一步研究AF6 PDZ结构域抑制剂。与TP 9合作（Birchmeier，von Kries），将对DINEVELED（DVL9）的抑制剂（DVL9）进行研究。 Shank3在突触后密度中的作用将与柏林神经计划的Dietmar Schmitz一起研究。通过计算方法鉴定PDZ域的选择性模式将有助于进一步发展更具体的抑制剂。 NMR谱研究，计算机辅助配体设计和医学化学的周期将产生特定的配体。作为模型情况，我们将开发与Cal结合但不与NHERF结合的特定配体，两种蛋白质在囊性纤维化中起着至关重要的作用。

项目成果

Small‐Molecule Inhibitors of AF6 PDZ‐Mediated Protein–Protein Interactions

AF6 PDZ 介导的蛋白质相互作用的小分子抑制剂

• DOI: 10.1002/cmdc.201300553
• 发表时间: 2014
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Vargas;Radziwill;Krause;Keller;Kamdem;Czekelius;Kreuchwig;Schmieder;Moelling;Schade;Oschkinat
• 通讯作者: Oschkinat