Biological Effects of a Simplified Synthetic Analogue of Ion‐Channel‐Forming Polytheonamide B on Plasma Membrane and Lysosomes.

Xue, Yun‐Wei; Hayata, Atsushi; Itoh, Hiroaki; Inoue, Masayuki

Polytheonamide B (1) is a linear 48‐mer natural peptide with alternating d‐ and l‐amino acid residues. Compound 1 forms conducting channels for monovalent ions and exhibits potent cytotoxicity against MCF‐7 cells. Previously, we reported that nanomolar concentrations of 1 induce plasma membrane depolarization and lysosomal pH disruption, which triggers apoptosis. Here, we report the cellular localization and biological action of a simplified synthetic analogue of 1, polytheonamide mimic 3. Compared with 1, the toxicity of 3 against MCF‐7 cells is 16 times weaker. Although its plasma membrane depolarization effect is only 3.6 times lower, more 3 (20‐fold) is required to neutralize lysosomal pH. Thus, the effective concentrations for lysosomal neutralization and cytotoxicity by 3 are comparable. These results strongly suggest that the activity of 3 against the lysosomal membrane is more important for apoptotic cell death than its effects on the plasma membrane, and provide valuable information regarding the unique behavior of polytheonamide‐based molecules.

CELL membranes; ION channels; CELL death; LYSOSOMES

Chemistry - A European Journal, 2019, Vol 25, Issue 66, p15198

0947-6539

Academic Journal

10.1002/chem.201903974