Graduate School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan; Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa 210-9501, Japan.
Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Kanagawa 210-9501, Japan.
Bioorg Med Chem. 2022 Nov 1;73:117021. doi: 10.1016/j.bmc.2022.117021. Epub 2022 Sep 28.
Wnt/β-catenin pathway triggers the formation of a complex between β-catenin and T cell-specific transcription factor (TCF), which induces transcriptional activation. Excessive transcriptional activation of this pathway is associated with the development, cause, and deterioration of various cancers. Therefore, the Wnt/β-catenin pathway is an attractive drug target for cancer therapeutics and small molecule- and peptide-based protein-protein interaction (PPI) inhibitors have been developed. However, peptide-based PPI inhibitors generally have low cell-membrane permeability because of their large molecular size. To improve cell-membrane permeability, conjugating cell-penetrating peptides (CPPs) to PPI-inhibiting peptides is a useful method for developing intracellularly targeted PPI inhibitors. In this study, we focused on the interaction between β-catenin and liver receptor homologue-1 (LRH-1) and designed and synthesized a series of LRH-1-derived peptides to develop inhibitors against Wnt/β-catenin signaling. The results showed that a penetratin-conjugated LRH-1-derived peptide (Penetratin-st7) predominantly inhibited DLD-1 cell growth at 20 μM treatment via inhibition of the Wnt signaling pathway. This result suggests that Penetratin-st7 is one of promising PPI inhibitors between TCF and β-catenin.
Wnt/β-catenin 通路触发β-catenin 与 T 细胞特异性转录因子（TCF）形成复合物，从而诱导转录激活。该通路的过度转录激活与各种癌症的发生、发展和恶化有关。因此，Wnt/β-catenin 通路是癌症治疗的一个有吸引力的药物靶点，已经开发出了基于小分子和肽的蛋白质-蛋白质相互作用（PPI）抑制剂。然而，由于其分子尺寸较大，基于肽的 PPI 抑制剂通常细胞膜通透性较低。为了提高细胞膜通透性，将细胞穿透肽（CPP）与 PPI 抑制肽缀合是开发细胞内靶向 PPI 抑制剂的一种有效方法。在这项研究中，我们专注于β-catenin 和肝受体同源物-1（LRH-1）之间的相互作用，并设计和合成了一系列 LRH-1 衍生肽，以开发针对 Wnt/β-catenin 信号通路的抑制剂。结果表明，Penetratin 缀合的 LRH-1 衍生肽（Penetratin-st7）在 20 μM 处理时通过抑制 Wnt 信号通路，主要抑制 DLD-1 细胞生长，抑制率为 20 μM。这一结果表明，Penetratin-st7 是 TCF 和 β-catenin 之间有前途的 PPI 抑制剂之一。
