Photoswitchable Calixarene Activators for Controlled Peptide Transport across Lipid Membranes

Supramolecular synthetic transporters are crucial tounderstandand activate the passage across lipid membranes of hydrophilic effectormolecules. Herein, we introduce photoswitchable calixarenes for thelight-controlled transport activation of cationic peptide cargos acrossmodel lipid bilayers and inside living cells. Our approach was basedon rationally designed p-sulfonatocalix[4]arene receptorsequipped with a hydrophobic azobenzene arm, which recognize cationicpeptide sequences at the nM range. Activation of membrane peptidetransport is confirmed, in synthetic vesicles and living cells, forcalixarene activators featuring the azobenzene arm in the E configuration. Therefore, this method allows the modulationof the transmembrane transport of peptide cargos upon Z-E photoisomerization of functionalized calixarenesusing 500 nm visible light. These results showcase the potential ofphotoswitchable counterion activators for the light-triggered deliveryof hydrophilic biomolecules and pave the way for potential applicationsin remotely controlled membrane transport and photopharmacology applicationsof hydrophilic functional biomolecules.