Histidine-Rich Designer Peptides with pH-Dependent Membrane Topology, Antimicrobial, Nucleic Acid Transfection and Viral Transduction Capabilities

The synthetic LAH4 peptides were designed to investigate the interactions that determine the membrane topology of helical peptides (1). Their core consist of alanines, leucine and four histidines arranged to form an amphipathic helix, as well as two lysines at each terminus. Through protonation of its histidines (pKs between 5.4 and 6.0) the alignment of the helices is transmembrane at neutral pH and in-plane at pH <5.5 (1).The LAH4 peptides exhibit membrane pore-formation and antimicrobial action at both neutral and at acidic pH including against clinical isolates where the low pH configuration is more active (2). The LAH4 peptides have been found to also exhibit potent DNA and siRNA transfection activities (3). LAH4 can therefore act as a non-viral vector and has indeed been used for the delivery of quantum dots or protein-based vaccines. Furthermore, transduction by adeno-associated viruses or lentiviruses is enhanced by LAH4 peptides (4). Ongoing biophysical and structural investigations will be reported which aim to understand these activities at atomic resolution (5-8).1. B. Bechinger, J.Mol.Biol. 263, 768 (1996).2. A. J. Mason, et al., J. Biol. Chem. 284, 119 (2009).3. B. Bechinger, V. Vidovic, P. Bertani, A. Kichler, J Pept Sci 17, 88 (2011).4. D. Fenard, D. Ingrao, A. Seye, J. Buisset, S. Genries, S. Martin, A. Kichler, A. Galy, Molecular Therapy-Nucleic Acids 2, doi:10.1038/mtna.2013.17 (2013).5. C. Aisenbrey, B. Bechinger, Langmuir 30, 10374 (2014).6. R. Machaň, P. Jurkiewicz, T. Steinberger, B. Bechinger, M. Hof, Langmuir 30, 6171 (2014).7. B. Perrone, A. J. Miles, E. Salnikov, B. Wallace, B. Bechinger, Eur. Biophys. J. epub. Sep. 3, (2014).8. A. Farrotti, G. Bocchinfuso, A. Palleschi, N. Rosato, E. Salnikov, N. Voievoda, B. Bechinger, L. Stella, (2014, submitted).