Insights into the anticancer properties of the first antimicrobial peptide from Archaea

Background:The peptide VLL-28, identified in the sequence of an archaeal protein, the transcription factor Stf76fromSulfolobus islandicus, was previously identified and characterized as an antimicrobial peptide, possessing abroad-spectrum antibacterial activity.Methods:Through a combined approach of NMR and Circular Dichroism spectroscopy, Dynamic LightScattering, confocal microscopy and cell viability assays, the interaction of VLL-28 with the membranes of bothparental and malignant cell lines has been characterized and peptide mechanism of action has been studied.Results:It is here demonstrated that VLL-28 selectively exerts cytotoxic activity against murine and humantumor cells. By means of structural methodologies, VLL-28 interaction with the membranes has been proven andthe binding residues have been identified. Confocal microscopy data show that VLL-28 is internalized only intotumor cells. Finally, it is shown that cell death is mainly caused by a time-dependent activation of apoptoticpathways.Conclusions:VLL-28, deriving from the archaeal kingdom, is here found to be endowed with selective cytotoxicactivity towards both murine and human cancer cells and consequently can be classified as an ACP.General significance:VLL-28 represents thefirst ACP identified in an archaeal microorganism, exerting a trans-kingdom activity