Lipid membrane and lipopolysaccharide (LPS) interactions were investigated for a series of amphiphilic and cationic peptides derived from human heparin cofactor II, using dual polarization interferometry, ellipsometry, circular dichroism (CD), cryoTEM, and z-potential measurements. Antimicrobial effects of these peptides were compared to their ability to disorder bacterial lipid membranes, while their capacity to block endotoxic effects of LPS was correlated to the binding of these peptides to LPS and its lipid A moiety, and to charge, secondary structure, and morphology of peptide/LPS complexes. In particular, fragmentation and densification of LPS aggregates correlate to the anti-endotoxic effect of these peptides, thus identifying peptide-induced packing transitions in LPS aggregates as key for anti-endotoxic functionality. PEGylation of these peptides reduces peptide binding to lipid membranes, an effect accentuated at increasing PEG length but less sensitive to conjugation site. The reduced binding causes suppressed liposome leakage induction, as well as bacterial lysis. As a result of this, the antimicrobial effects of KYE28 is partially lost with increasing PEG length, but hemolysis also strongly suppressed and selecticity improved. Through this, conditions can be found, at which the PEGylated peptide displays simultaneously efficient antimicrobial affects and low hemolysis in blood. Importantly, PEGylation does not markedly affect the anti-inflammatory effects of these peptides. The combination of reduced toxicity, increased selectivity, and retained anti-inflammatory effect after PEGylation, thus shows that PEG conjugation may offer opportunities in the development of effective and selective anti-inflammatory peptides.<br/>

Importance of lipopolysaccharide aggregate disruption for the anti-endotoxic effects of host defense peptides

251st National Meeting (2016)

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