2026-03-23 静岡大学
図１．(A) ADIの特徴 (B) 水素結合能
＜関連情報＞
- https://www.shizuoka.ac.jp/news/detail.html?CN=11751
- https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c02090
膜透過性を向上させるためのペプチド骨格修飾におけるアミドからクロロアルケンへの置換 Amide-to-Chloroalkene Substitution for Peptide Backbone Modification to Enhance Membrane Permeability
Sayuri Takeo,Mio Takeda,Chihiro Iio,Ai Sakakibara,Showmitra Saha,Natsuki Shibata,Yuki Yamazaki,Takahiro Fujii,Ryuhei Harada,Kohei Sato,Nobuyuki Mase,Mizuki Watanabe,Takanori Oyoshi,Tetsuo Narumi
Journal of Medicinal Chemistry Published: February 20, 2026
DOI:https://doi.org/10.1021/acs.jmedchem.5c02090
Abstract
Herein, we report a systematic evaluation of backbone modification strategies to enhance peptide membrane permeability, focusing on chloroalkene dipeptide isosteres (CADIs) as amide bond surrogates. A direct comparison with classical modifications─including N-methylation, esterification, and thioamidation─reveals that CADI substitution consistently provides the highest improvement in both passive diffusion and cellular uptake. Mechanistic analyses combining A log P calculations, HPLC profiling, and molecular dynamics simulations attribute this effect primarily to improved lipophilicity and reduced hydration, rather than conformational changes. Notably, CADI substitution is successfully extended to longer polar sequences and cyclic scaffolds, and it preserves or enhances RNA-binding affinity and selectivity in G-quadruplex-binding RGG peptides. Overall, this study establishes CADI substitution as a robust backbone modification strategy that enables the design of peptidomimetics with enhanced membrane permeability and improved resistance to hydrolytic stability.
