Modified Peptides as Potent Inhibitors of the Postsynaptic Density-95/N-Methyl-D-Aspartate Receptor Interaction
Modified Peptides as Potent Inhibitors of the Postsynaptic Density-95/N-Methyl-D-Aspartate Receptor Interaction
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DOI：
10.1021/jm800836w
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发表时间：
2008-10-23
影响因子：
7.3
通讯作者：
Stromgaard, Kristian
中科院分区：
文献类型：
--
作者：
Bach, Anders;Chi, Celestine N.;Stromgaard, Kristian
NMDA受体与其细胞内支架蛋白PSD-95之间的蛋白-蛋白相互作用是治疗缺血性脑疾病的潜在靶点。NMDA c端对应的非肽被用作模板，以寻找抑制PSD-95/NMDA受体相互作用的先导候选物。最初，进行了截断和丙氨酸扫描研究，结果产生了具有野生型亲和力的五肽，如荧光偏振测定所示。通过对天然和非天然氨基酸的系统取代进行进一步的研究，发现具有微摩尔亲和力的三肽和具有改善亲和力的n -甲基化四肽。分子模型研究指导了进一步的n端修饰和一系列n端取代的引入，极大地提高了亲和力。最佳化合物n -环己基乙基- etav（56）显示，与野生型相比，K-i值降低了19倍（对PSD-95的PDZ1和PDZ2的K-i分别为0.94和0.45 μ M），是迄今为止报道的最有效的相互作用抑制剂。这些新型有效抑制剂为PSD-95/NMDA受体相互作用小分子抑制剂的开发提供了重要基础。
The protein-protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treatment of ischemic brain diseases. An undecapeptide corresponding to the C-terminal of the NMDA was used as a template for finding lead candidates for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound, N-cyclohexylethyl-ETAV (56), demonstrated up to 19-fold lower K-i value (K-i = 0.94 and 0.45 mu M against PDZ1 and PDZ2 of PSD-95, respectively) compared to wild-type values, providing the most potent inhibitors of this interaction reported so far. These novel and potent inhibitors provide an important basis for development of small molecule inhibitors of the PSD-95/NMDA receptor interaction.