Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions
Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions
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DOI：
10.1073/pnas.1934759100
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发表时间：
2003-09-30
影响因子：
11.1
通讯作者：
Spatola, AF
中科院分区：
文献类型：
--
作者：
Leduc, AM;Trent, JO;Spatola, AF
核受体和辅活化剂之间的相互作用提供了一个竞技场，用于测试蛋白质-蛋白质相互作用是否可以被小分子候选药物抑制。我们提供的证据表明，一个短的环状肽，含有一个副本的LXXLL核受体盒五肽，紧密结合，并选择性地雌激素受体a。此外，如X射线分析所示，二硫键桥接的九肽，在水溶液中的非螺旋，能够采用准螺旋构象异构体，同时结合到由配体附着到雌激素受体α所产生的凹槽。i，i+3连接的类似物H-Lys-环（D-CYS-Ile-Leu-Cys）-Arg-Leu-Leu-Gln-NH 2（拟肽雌激素受体调节剂1）以25 nM的Ki结合，显著优于i，i+4桥接的环酰胺，如通过分子建模设计标准所预测的。这种肽类似物所表现出的螺旋特征、有效结合和受体选择性的诱导为这种策略提供了强有力的支持。最低限度的表面图案的稳定可能被证明是有用的控制其他大分子组装，特别是当一个两亲性的螺旋是至关重要的两个蛋白质之间的强结合相互作用。
The interaction between nuclear receptors and coactivators provide; an arena for testing whether protein-protein interactions may be inhibited by small molecule drug candidates. We provide evidence that a short cyclic peptide, containing a copy of the LXXLL nuclear receptor box pentapeptide, binds tightly and selectively to estrogen receptor a. Furthermore, as shown by x-ray analysis, the disulfide-bridged nonapeptide, nonhelical in aqueous solutions, is able to adopt a quasihelical conformer while binding to the groove created by ligand attachment to estrogen receptor alpha. An i, i+3 linked analog, H-Lys-cyclo(D-CYS-Ile-Leu-Cys)-Arg-Leu-Leu-Gin-NH2 (pepcidomimetic estrogen receptor modulator 1), binds with a K-i of 25 nM, significantly better than an i, i+4 bridged cyclic amide, as predicted by molecular modeling design criteria. The induction of helical character, effective binding, and receptor selectivity exhibited by this peptide analog provide strong support for this strategy. The stabilization of minimalist surface motifs may prove useful for the control of other macromolecular assemblies, especially when an amphiphilic helix is crucial for the strong binding interaction between two proteins.