Cell-Selective Pore Forming Antimicrobial Peptides of the Prodomain of Human Furin: A Conserved Aromatic/Cationic Sequence Mapping, Membrane Disruption, and Atomic-Resolution Structure and Dynamics.

Antimicrobial peptides are promising molecules in uprising consequences of drug-resistant bacteria. The prodomain of furin, a serine protease, expressed in all vertebrates including humans, is known to be important for physiological functions. Here, potent antimicrobial peptides were mapped by extensive analyses of overlapping peptide fragments of the prodomain of human furin. Two peptides, YR26 and YR23, were active against bacterial cells including MRSA-resistant and 51625. Peptides were largely devoid of hemolytic and cytotoxic activity. Bacterial cell killing occurred as a result of the disruption of the permeability barrier of the lipopolysaccharide (LPS)-outer membrane and fragmentation of LPS into small micelles. Furthermore, antibacterial peptides specifically interacted with the negatively charged lipids causing membrane leakage and fusion. The YR26 peptide in sodium dodecyl sulfate micelles demonstrated a long-helix-turn-short-helix structure exhibiting restricted backbone motions. The cell-selective activity of the furin peptides and their unique mode of action on membranes have a significant potential for the development of therapeutics.