Abstract
BP100 is a short, designer-made membrane-active peptide with multiple functionalities: antimicrobial, cell-penetrating, and fusogenic. Consisting of five lysines and 6 hydrophobic residues, BP100 was shown to bind to lipid bilayers as an amphipathic α-helix, but its mechanism of action remains unclear. With these features, BP100 embodies the characteristics of two distinctly different classes of membrane-active peptides, which have been studied in detail and where the mechanism of action is better understood. On the one hand, its amphiphilic helical structure is similar to the pore forming magainin family of antimicrobial peptides, though BP100 is much too short to span the membrane. On the other hand, its length and high charge density are reminiscent of the HIV-TAT family of cell penetrating peptides, for which inverted micelles have been postulated as translocation intermediates, amongst other mechanisms. Assays were performed to test the antimicrobial and hemolytic activity, the induced leakage and fusion of lipid vesicles, and cell uptake. From these results the functional profiles of BP100, HIV-TAT, and the magainin-like peptides magainin 2, PGLa, MSI-103, and MAP were determined and compared. It is observed that the activity of BP100 resembles most closely the much longer amphipathic α-helical magainin-like peptides, with high antimicrobial activity along with considerable fusogenic and hemolytic effects. In contrast, HIV-TAT shows almost no antimicrobial, fusogenic, or hemolytic effects. We conclude that the amphipathic helix of BP100 has a similar membrane-based activity as magainin-like peptides and may have a similar mechanism of action.
Highlights
Membrane-active peptides tend to have short sequences and simple secondary structures, from which it often appears straightforward to predict their mechanism of membrane-perturbation
We here used three bacterial strains to compare the antimicrobial activity of BP100 with those of other well-known Antimicrobial peptides (AMPs) and Cell-penetrating peptides (CPPs)
TAT, on the other hand, which consists of 13 amino acids and is largely unstructured, can enter the cytosol efficiently and has no significant membranolytic effects, i.e., it does not kill bacteria or induce hemolysis as seen in several assays used here
Summary
Membrane-active peptides tend to have short sequences and simple secondary structures, from which it often appears straightforward to predict their mechanism of membrane-perturbation. We studied the short yet highly helical peptide BP100, which shares some striking similarities with two distinctly different classes of membrane-active peptides: (i) well-structured amphiphilic helical peptides such as magainin 2 (Zasloff, 1987), and (ii) short, highly charged cell penetrating peptides such as HIV-TAT (Vives et al, 1997; Thorén et al, 2003). Many CPPs show antimicrobial activity and vice versa, depending on which cell type and lipid composition they encounter (Nekhotiaeva et al, 2004; Henriques et al, 2006; Strandberg et al, 2007; Wadhwani et al, 2012a). Many FPs are rich in Gly and have a rather flexible structure (Reichert et al, 2007), but they share many similarities with AMPs and CPPs (Wadhwani et al, 2012b)
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