Enzyme-modulate conformational changes in amphiphile peptide for selectively cell delivery

Achieving selectivity in cell penetrating peptide (CPP) design is crucial to mitigate systemic toxicity and enable precise targeting based on distinct cellular phenotypes. Herein, we designed an amphiphilic peptide, L17Yp, by incorporating phosphorylated tyrosine into natural occurring M-lycotoxin peptide, known for its potent membrane-lytic activity. This strategic modification induced a conformational shift, as confirmed by circular dichroism spectroscopy, transitioning it from its bioactive α-helix conformation to an inactive random coli configuration, effectively shielding its membrane-penetrating capacity. Upon exposure to alkaline phosphatase, L17Yp undergoes enzymatic dephosphorylation, prompting a conformational shift that restores its membrane-transduction capabilities. This unique property hold promises for selective drug delivery. This work introduces an enzymatic approach for targeted perturbation of the cell membrane, offering promising prospects for precise drug delivery applications.