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An electrochemical study into the interaction between complement-derived peptides and DOPC mono- and bilayers.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2008 (English)In: Langmuir, ISSN 0743-7463, Vol. 24, no 1, 208-216 p.Article in journal (Refereed) Published
Abstract [en]

Electrochemical methods employing the hanging mercury drop electrode were used to study the interaction between variants of the complement-derived antimicrobial peptide CNY21 (CNYITELRRQH ARASHLGLAR) and dioleoyl phosphatidylcholine (DOPC) monolayers. Capacitance potential and impedance measurements showed that the CNY21 analogues investigated interact with DOPC monolayers coating the mercury drop. Increasing the peptide hydrophobicity by substituting the two histidine residues with leucine resulted in a deeper peptide penetration into the hydrophobic region of the DOPC monolayer, indicated by an increase in the dielectric constant of the lipid monolayer (Deltaepsilon = 2.0 after 15 min interaction). Increasing the peptide net charge from +3 to +5 by replacing the histidines by lysines, on the other hand, arrests the peptide in the lipid head group region. Reduction of electroactive ions (Tl+, Pb2+, Cd2+, and Eu3+) at the monolayer-coated electrode was employed to further characterize the types of defects induced by the peptides. All peptides studied permeabilize the monolayer to Tl+ to an appreciable extent, but this effect is more pronounced for the more hydrophobic peptide (CNY21L), which also allows penetration of larger ions and ions of higher valency. The results for the various ions indicate that charge repulsion rather than ion size is the determining factor for cation penetration through peptide-induced defects in the DOPC monolayer. The effects obtained for monolayers were compared to results obtained with bilayers from liposome leakage and circular dichroism studies for unilamellar DOPC vesicles, and in situ ellipsometry for supported DOPC bilayers. Trends in peptide-induced liposome leakage were similar to peptide effects on electrochemical impedance and permeability of electroactive ions for the monolayer system, demonstrating that formation of transmembrane pores alone does not constitute the mechanism of action for the peptides investigated. Instead, our results point to the importance of local packing defects in the lipid membrane in close proximity to the adsorbed peptide molecules.

Place, publisher, year, edition, pages
2008. Vol. 24, no 1, 208-216 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-86865DOI: 10.1021/la702538kISI: 000251916100032PubMedID: 18052298OAI: oai:DiVA.org:uu-86865DiVA: diva2:127524
Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2010-01-18Bibliographically approved
In thesis
1. Interaction Between Antimicrobial Peptides and Phospholipid Membranes: Effects of Peptide Length and Composition
Open this publication in new window or tab >>Interaction Between Antimicrobial Peptides and Phospholipid Membranes: Effects of Peptide Length and Composition
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Due to increasing problems with bacterial resistance development, there is a growing need for identifying new types of antibiotics. Antimicrobial peptides constitute an interesting group of substances for this purpose, since they are believed to act mainly by disrupting the bacterial membrane, which is a fast and non-specific mechanism. In order to understand the details on this action simplified phospholipid model membranes based on liposomes, monolayers and bilayers, were employed in this thesis.

By in situ ellipsometry studies on supported lipid bilayers in combination with leakage from liposomes it was found that peptide-induced membrane rupture to a great extent is related to peptide adsorption. The peptide activity and mechanism of action is highly dependent on peptide properties such as length, topology, charge, and hydrophobicity. Electrostatic interactions are crucial for peptide adsorption, whereas α-helix formation is of less importance, demonstrated by the dominating peptide conformation being random coil both in absence and presence of membranes, as investigated by circular dichroism. Comparable effects were observed in both mono- and bilayer systems, showing that formation of transmembrane structures is no prerequisite for membrane rupture by complement-derived peptides. Electrochemical studies on these peptides further demonstrated that hydrophobic interactions facilitate peptide penetration into the membrane, causing defects in close proximity to the peptides, while strong electrostatic interactions arrest the peptide in the headgroup region. Increasing the peptide hydrophobicity, by e.g., tryptophan end-tagging, also increases salt resistance.

Good correlations were found between model membrane investigations and antibacterial activity towards both Gram-negative and Gram-positive bacteria, showing that membrane rupture is a key mechanism of action for the peptides investigated. In addition, for all peptides investigated cell toxicity is low.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 101
Series
Keyword
Adsorption, antibacterial, antimicrobial peptide, bilayer, ellipsometry, electrochemistry, electrostatic interactions, hydrophobicity, liposome, membrane, monolayer, phospholipid, secondary structure, supported bilayer.
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-101989 (URN)978-91-554-7540-6 (ISBN)
Public defence
2009-06-12, B42, Biomedical Center, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-05-18 Created: 2009-04-29 Last updated: 2009-05-18Bibliographically approved

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