Over the course of evolutionary history, humans and bacteria have shared a symbiotic relationship. Often this balance is altered, giving way to pathogenic bacteria to blossom. With the widespread use of antibiotics in recent decades, bacterial resistance has become a noteworthy global health concern. Antimicrobial peptides have emerged as a promising alternative to conventional antibiotics and insight into their mechanism of action upon membrane interaction can be used for the design of potent analogs. However, the mechanistic aspects of their biological roles remain unclear.<br/>In order to systematically study these molecules, the LAH4-Ax and LAH4-Lx family of amphipathic peptides have been designed to predominantly acquire α-helical conformations in phospholipid environments and modify their membrane topology in a pH-dependent manner. We report on their membrane disruption capabilities with calcein release assays in POPC/POPS membrane models at a 3:1 molar ratio and antimicrobial activity against <i>Escherichia coli.</i> In addition, we were able to investigate possible correlations with the polar angle between the histidines and the mean helical hydrophobic moment, as well as their transduction enhancing capabilities in the VSV-G-LV and GALVTR-LV lentiviral pseudotypes that have respectively, pH-dependent and pH-independent viral entry pathways.<br/>Our findings indicate that the critical determinants for lentiviral transduction are possibly different from those essential for membrane disruption or antibiotic activity of the LAH4 derivatives. Furthermore, results point to complex membrane-peptide interactions and the possibility of different mechanisms of action. In-depth investigations that analyze other molecular determinants are necessary to shed light on the mechanisms of action, given the potential of the LAH4 amphipathic peptides for an array of biological and biomedical applications.

Interactions of LAH4-Lx and LAH4-Ax family of histidine-rich amphipathic peptides with biomembrane models

251st National Meeting (2016)

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