Development of a penetratin-conjugated stapled peptide that inhibits Wnt/β-catenin signaling. (1st November 2022)

• Record Type: Journal Article
• Authors: Tsuchiya, Keisuke; Kiyoshi, Masato; Hashii, Noritaka; Fujita, Minami; Kurohara, Takashi; Ishii-Watabe, Akiko; Fukuhara, Kiyoshi; Misawa, Takashi; Demizu, Yosuke
• Is Part Of: Bioorganic & medicinal chemistry. Volume 73(2022)
• Publication Date: 2022-11-01
• Subjects: Cell-penetrating peptide -- CPP-conjugated peptide -- Protein–protein interaction -- Stapled peptide -- Wnt/β-catenin signaling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117021
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.