Abstract
Membrane active peptides are of large interest for development of drug delivery vehicles and therapeutics for treatment of multiple drug resistant infections. Lack of specificity can be detrimental and finding routes to tune specificity and activity of membrane active peptides is vital for improving their therapeutic efficacy and minimize harmful side effects. We describe a de novo designed membrane active peptide that partition into lipid membranes only when specifically and covalently anchored to the membrane, resulting in pore-formation. Dimerization with a complementary peptide efficiently inhibits formation of pores. The effect can be regulated by proteolytic digestion of the inhibitory peptide by the matrix metalloproteinase MMP-7, an enzyme upregulated in many malignant tumors. This system thus provides a precise and specific route for tuning the permeability of lipid membranes and a novel strategy for development of recognition based membrane active peptides and indirect enzymatically controlled release of liposomal cargo.
Highlights
IntroductionA more suitable strategy to increase AMP membrane affinity and selectivity would be to trigger specific and high affinity binding of the peptides to species already present in the lipid membrane
Exposing carboxyfluorescein (CF) loaded liposomes prepared from zwitterionic POPC to JR2KC (4 μ M) showed that the peptide had limited effect on the membrane integrity and caused only minor release of CF (Fig. 2)
The maleimide moiety selectively reacts with the thiol group in the cysteine residue in the peptide loop region via a Michael addition, and covalently anchors the peptides to lipids in the membrane (Supplementary Fig. 2)
Summary
A more suitable strategy to increase AMP membrane affinity and selectivity would be to trigger specific and high affinity binding of the peptides to species already present in the lipid membrane. This is further motivated by the observations that AMPs, in addition to their bactericidal properties, can demonstrate adverse toxic effects on healthy non-pathogenic cells and exhibit undesirable and significant haemolytic activity[15]. In addition to demonstrating a possible path for obtaining more specific designer AMPs, this system enables enzyme mediated liposomal release The latter indicates a possible strategy for design of peptides for increasing efficacy of liposome-encapsulated anti-cancer drugs by increasing the release rate in the vicinity of tumors
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