Abstract

GL13K is a broad-spectrum antimicrobial peptide with selective bactericidal and antibiofilm activity, which makes it an attractive candidate for targeted antibiotic applications. Many antimicrobial peptides are multifunctional and have exhibited anticancer activity. Along with this precedent, GL13K’s potency on cancer has not been yet reported. Therefore, we proceeded to a preliminary assessment of anticancer activity for both D- and L-GL13K enantiomers in cancer cell lines. It emerged that D-GL13K showed selective toxicity in cancer cells. Such enantiomeric differences have previously been attributed to their resistance to proteolytic degradation. To probe if distinct mechanisms of interaction are involved in either their antibacterial vs anticancer activity, we evaluated the roles of peptide chirality and membrane composition by studying the interaction of D- and L-GL13K, as well as a newly designed GL28K peptide, with model membranes that mimic the lipid composition of those in human cancer, erythrocyte cells and bacteria. For this purpose, a combination of bulk and surface-specific biophysical techniques was used. The enantiomers showed differential interactions that can depend on the lipid composition in agreement with their activity (in the absence of proteases) as evidenced by greater binding and insertion in the cancer model membranes. However, in contrast to results in bacterial models neither enantiomer of GL13K displayed a crystalline beta-sheet conformation in presence of the eukaryotic cell model, despite this being a hallmark of their activity with bacterial models. The molecular origins and significance of these results will be discussed.