Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors.
Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors.
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DOI：
10.1021/ja107761h
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发表时间：
2011-02-23
影响因子：
15
通讯作者：
Zhou MM
中科院分区：
文献类型：
--
作者：
Gerona-Navarro G;Yoel-Rodríguez;Mujtaba S;Frasca A;Patel J;Zeng L;Plotnikov AN;Osman R;Zhou MM
CREB结合蛋白（CREB binding protein， CBP）是一种人类转录共激活因子，由几个保守的功能模块组成，可与不同的转录因子相互作用，包括核受体、CREB和STAT蛋白。尽管CBP在转录调控中的重要性，但关于其特定结构域在CBP功能中的作用的许多问题仍未得到解答。因此，开发能够选择性调节CBP单一结构域的小分子对于揭示其突出活动具有宝贵的帮助。本文报道了构象限制肽作为CBP乙酰赖氨酸结合溴域（BRD）的新型调节剂的设计、合成和生物学评价。利用目标结构引导和计算机辅助的合理设计方法，我们开发了一系列环肽，其对CBP BRD的亲和力显著高于其生物配体，包括赖氨酸乙酰化组蛋白和肿瘤抑制因子p53。该系列中最好的环肽Kd为8.0µM，与线性赖氨酸382乙酰化的p53肽相比，亲和度提高了24倍。与其他转录蛋白的BRD相比，该先导肽对CBP BRD具有高度选择性。在结直肠癌HCT116细胞中进行的基于细胞的功能分析进一步证明了该化合物在DNA损伤下调节p53稳定性和功能的功效。我们的研究结果强烈表明，这些CBP调节剂可以通过阻断p53K382ac与CBP BRD的结合，并通过改变其翻译后修饰状态来促进p53的不稳定性，从而有效地抑制p53的转录活性，这与目前报道的p53抑制剂的机制不同。
The CREB binding protein (CBP) is a human transcriptional co-activator consisting of several conserved functional modules, which interacts with distinct transcription factors including nuclear receptors, CREB, and STAT proteins. Despite the importance of CBP in transcriptional regulation, many questions regarding the role of its particular domains in CBP functions remain unanswered. Therefore, developing small molecules capable of selectively modulating a single domain of CBP is of invaluable aid at unraveling its prominent activities. Here we report the design, synthesis and biological evaluation of conformationally restricted peptides as novel modulators for the acetyl-lysine binding bromodomain (BRD) of CBP. Utilizing a target structure–guided and computer-aided rational design approach, we developed a series of cyclic peptides with affinity for CBP BRD significantly greater than those of its biological ligands, including lysine-acetylated histones and tumor suppressor p53. The best cyclopeptide of the series exhibited a Kd of 8.0 µM, representing a 24-fold improvement in affinity over that of the linear lysine 382-acetylated p53 peptide. This lead peptide is highly selective for CBP BRD over BRDs from other transcriptional proteins. Cell-based functional assays carried out in colorectal carcinoma HCT116 cells further demonstrated the efficacy of this compound to modulate p53 stability and function in response to DNA damage. Our results strongly argue that these CBP modulators can effectively inhibit p53 transcriptional activity by blocking p53K382ac binding to CBP BRD and promoting p53 instability by changes of its post-translational modification states, a different mechanism to that of the p53 inhibitors reported to date.
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影响因子：
64.8
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作者：
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