ダウンロード数: 188
このアイテムのファイル:
ファイル | 記述 | サイズ | フォーマット | |
---|---|---|---|---|
acs.molpharmaceut.1c00671.pdf | 3.03 MB | Adobe PDF | 見る/開く |
タイトル: | Grafting Hydrophobic Amino Acids Critical for Inhibition of Protein–Protein Interactions on a Cell-Penetrating Peptide Scaffold |
著者: | Nagano, Yuki Arafiles, Jan Vincent V. Kuwata, Keiko Kawaguchi, Yoshimasa Imanishi, Miki https://orcid.org/0000-0002-4172-0966 (unconfirmed) Hirose, Hisaaki Futaki, Shiroh |
著者名の別形: | 長野, 由季 今西, 未来 川口, 祥正 廣瀨, 久昭 二木, 史朗 |
キーワード: | stapled peptide cell-penetrating peptide apoptosis nesprin-2 β-catenin |
発行日: | Feb-2022 |
出版者: | American Chemical Society (ACS) |
誌名: | Molecular Pharmaceutics |
巻: | 19 |
号: | 2 |
開始ページ: | 558 |
終了ページ: | 567 |
抄録: | Stapled peptides are a promising class of conformationally restricted peptides for modulating protein-protein interactions (PPIs). However, the low membrane permeability of these peptides is an obstacle to their therapeutic applications. It is common that only a few hydrophobic amino acid residues are mandatory for stapled peptides to bind to their target proteins. Hoping to create a novel class of membrane-permeable PPI inhibitors, the phenylalanine, tryptophan, and leucine residues that play a critical role in inhibiting the p53-HDM2 interaction were grafted into the framework of CADY2─a cell-penetrating peptide (CPP) having a helical propensity. Two analogues (CADY-3FWL and CADY-10FWL) induced apoptotic cell death but lacked the intended HDM2 interaction. Pull-down experiments followed by proteomic analysis led to the elucidation of nesprin-2 as a candidate binding target. Nesprin-2 is considered to play a role in the nuclear translocation of β-catenin upon activation of the Wnt signaling pathway, which leads to the expression of antiapoptosis proteins and cell survival. Cells treated with the two analogues showed decreased nuclear localization of β-catenin and reduced mRNA expression of related antiapoptotic proteins. These data suggest inhibition of β-catenin nuclear translocation as a possible mode of action of the described cell-penetrating stapled peptides. |
著作権等: | This document is the Accepted Manuscript version of a Published Work that appeared in final form in 'Molecular Pharmaceutics', copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.molpharmaceut.1c00671. The full-text file will be made open to the public on 27 December 2022 in accordance with publisher's 'Terms and Conditions for Self-Archiving' This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 |
URI: | http://hdl.handle.net/2433/274856 |
DOI(出版社版): | 10.1021/acs.molpharmaceut.1c00671 |
PubMed ID: | 34958576 |
出現コレクション: | 学術雑誌掲載論文等 |
このリポジトリに保管されているアイテムはすべて著作権により保護されています。