Melittin is a well-studied α-helical lytic peptide toxin that permeabilizes the cell membrane by forming membrane spanning pores. Its central proline residue (P14), which induces a kink in the helix, is also critical for its membrane activity. In addition to being the only cyclic amino acid proline can readily form the cis-amide bond. Azobenzene is a photoisomerizable molecule that switches from the trans to cis isomer upon excitation with ultraviolet-light (UV) and from the cis to trans isomer upon excitation with visible light (VL). In this work we replace P14 in melittin with an azobenzene amino acid (Z14) to create a novel photoisomerizable membrane active peptide: photomelittin. The secondary structure of the peptide was maintained while the membrane binding affinity was reduced compared to melittin. The peptide displayed light-dependent activity in vesicle leakage and hemolysis assays. A 1.5-fold increase in activity was observed in UV treated photomelittin in vesicle leakage assays while a 1.2-fold increase in activity was observed for VL treated photomelittin in hemolysis assays. This work provides a foundation for future studies optimizing photomelittin and other proline-containing α-helical membrane active peptides for uses in photopharmacology.

Photomelittin: A photoswitchable membrane active peptide

ACS Spring 2022

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