An amide-to-chloroalkene substitution improves the peptide permeability

 

An amide-to-chloroalkene substitution improves the peptide permeability

Sayuri Takeo, Chihiro Iio, Ai Sakakibara, Mio Takeda, Yuki Yamazaki, Kohei Sato, Nobuyuki Mase, Mizuki Watanabe, Tetsuo Narumi

Chem Rxiv, 2024. DOI: 10.26434/chemrxiv-2024-l36zv

This study highlights the novel application of Chloroalkene Dipeptide Isosteres (CADIs) in enhancing peptide membrane permeability. Replacing the peptide bond with CADIs in model dipeptides significantly improved passive permeability. This enhancement is attributed to the increased lipophilicity provided by the CADI substitution, as confirmed by AlogP calculations and HPLC retention times. Molecular dynamics simulations further indicated that CADI substitution reduces water interaction, potentially lowering hydration energy. Our findings demonstrate that CADI incorporation can effectively improve the permeability of peptides, offering a valuable approach for developing bioactive peptidomimetics with enhanced pharmacological properties including permeability and hydrolytic stability.