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传导通路中发挥重要作用，天然肽配体结合到 ß 链和 C 端螺旋之间的脊中，该脊具有以下特性。在第一个资助期间鉴定了对多个 PDZ 结构域具有低至中等亲和力的小分子结合位点，并在 PDZ 库中收集了相应物质类别的成员。 AF6 PDZ 结构域抑制剂通过建模化学循环产生具有 10 至 20 微摩尔解离常数的化合物，破坏细胞裂解物中的 AF6-Bcr 相互作用。在第二个资助期，我们希望利用我们的结果并重点关注三个 PDZ 结构域（AF6、 DVL、Shank3），旨在了解各个蛋白质的生物学特性。将使用斑马在细胞生物学和体内实验中进一步研究 AF6 PDZ 结构域抑制剂。鱼模型（与 Ted Allison，艾伯塔省合作）将与 TP 9（Birchmeier，von Kries）合作研究 Shank3 在突触后密度中的作用。将与柏林 Neurocure 项目的 Dietmar Schmitz 一起进行研究，通过计算方法识别 PDZ 结构域的选择性模式将有助于进一步开发更具体的技术。作为模型案例，我们将开发与 CAL 但不与 NHERF 结合的特异性配体，这两种配体在囊性纤维化中发挥着至关重要的作用。

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