Rational Design and Structure Validation of a Novel Peptide Inhibitor of the Adenomatous-Polyposis-Coli (APC)-Rho-Guanine-Nucleotide-Exchange-Factor-4 (Asef) Interaction
Rational Design and Structure Validation of a Novel Peptide Inhibitor of the Adenomatous-Polyposis-Coli (APC)-Rho-Guanine-Nucleotide-Exchange-Factor-4 (Asef) Interaction
复制标题
腺瘤-息肉病-大肠杆菌 (APC)-Rho-鸟嘌呤-核苷酸-交换因子-4 (Asef) 相互作用的新型肽抑制剂的合理设计和结构验证
DOI：
10.1021/acs.jmedchem.8b01112
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发表时间：
2018
影响因子：
7.3
通讯作者：
Zhang Jian
中科院分区：
文献类型：
--
作者：
Yang Xiuyan;Zhong Jie;Zhang Qinfen;Qian Jinxing;Song Kun;Ruan Cong;Xu Jianrong;Ding Ke;Zhang Jian
在结直肠癌中，腺瘤性结肠息肉病（APC）与Rho鸟嘌呤核苷酸交换因子4（Asef）相互作用，从而刺激异常的结直肠癌细胞迁移。因此，APC-Asef相互作用代表了减轻结直肠癌迁移的有希望的治疗靶点。在本研究中，我们采用合理设计策略，包括引入分子内氢键和优化亲脂性取代基以提高肽的结合亲和力，从而发现MAI-400，其是迄今为止已知的APC-Asef相互作用的最佳抑制剂（Kd= 0.012 μM，IC 50 = 0.25 μM）。通过生物化学和生物物理测定对MAI-400进行的综合评价揭示了分子内氢键的形成和作用。基于细胞的测定显示MAI-400以剂量依赖性方式有效地阻断APC-Asef相互作用。因此，我们的研究提供了一个最好的同类抑制剂，MAI-400，基于合理的药物设计和结构验证，可以有效地抑制APC-Asef相互作用。
In colorectal cancer, adenomatous polyposis coli (APC) interacts with Rho guanine-nucleotide-exchange factor 4 (Asef), thereby stimulating aberrant colorectal-cancer-cell migration. Consequently, the APC–Asef interaction represents a promising therapeutic target for mitigating colorectal-cancer migration. In this study, we adopted the rational-design strategy involving the introduction of intramolecular hydrogen bonds and optimization of the lipophilic substituents to improve the binding affinities of peptides, leading to the discovery of MAI-400, the best inhibitor of the APC–Asef interaction known to date (Kd= 0.012 μM, IC50= 0.25 μM). Comprehensive evaluation of MAI-400 by biochemical and biophysical assays revealed the formation and effect of an intramolecular hydrogen bond. A cell-based assay showed MAI-400 efficiently blocking the APC–Asef interaction in a dose-dependent manner. Therefore, our study provides a best-in-class inhibitor, MAI-400, based on the rational drug design and structural validation, that can effectively inhibit the APC–Asef interaction.