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Effects of PEGylation on Membrane and Lipopolysaccharide Interactions of Host Defense Peptides
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2014 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 4, 1337-1345 p.Article in journal (Refereed) Published
Abstract [en]

Effects of poly(ethylene glycol) (PEG) conjugation on peptide interactions with lipid membranes and lipopolysaccharide (LPS) were investigated for KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR), an antimicrobial and anti-inflammatory peptide derived from human heparin cofactor II. In particular, effects of PEG length and localization was investigated by ellipsometry, circular dichroism, nanoparticle tracking analysis, and fluorescence/electron microscopy. PEGylation of KYE28 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 KYE28. The combination of reduced toxicity, increased selectivity, and retained anti-inflammatory effect after PEGylation, as well as reduced scavenging by serum proteins, thus shows that PEG conjugation may offer opportunities in the development of effective and selective anti-inflammatory peptides.

Place, publisher, year, edition, pages
2014. Vol. 15, no 4, 1337-1345 p.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-225069DOI: 10.1021/bm401884eISI: 000334571600026OAI: oai:DiVA.org:uu-225069DiVA: diva2:727590
Available from: 2014-06-23 Created: 2014-05-27 Last updated: 2016-06-01Bibliographically approved
In thesis
1. Amphiphilic Peptide Interactions with Complex Biological Membranes: Effect of peptide properties on antimicrobial and anti-inflammatory effects
Open this publication in new window or tab >>Amphiphilic Peptide Interactions with Complex Biological Membranes: Effect of peptide properties on antimicrobial and anti-inflammatory effects
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

With increasing problem of resistance development in bacteria against conventional antibiotics, as well as problems associated with diseases either triggered or enhanced by infection, there is an urgent need to identify new types of effective therapeutics for the treatment of infectious diseases and its consequences. Antimicrobial and anti-inflammatory peptides have attracted considerable interest as potential new antibiotics in this context. While antimicrobial function of such peptides is being increasingly understood demonstrated to be due to bacterial membrane disruption, the mechanisms of their anti-inflammatory function are poorly understood. Since bacterial membrane component lipopolysaccharide triggers inflammation, this thesis aims at clarifying importance of lipopolysaccharide (LPS)-peptide interactions while investigating possible modes of action of peptides exhibiting anti-inflammatory effect. Furthermore, effect of poly(ethylene)glycol (PEG)-conjugation was investigated to increase performance of such peptides.

Results presented in this thesis demonstrate that peptide-induced LPS- and lipid A binding/scavenging is necessary but not sufficient criterium for anti-inflammatory effects of peptides. Furthermore, preferential binding to LPS over lipid membrane, as well as higher binding affinity to the lipid A moiety within LPS, are seen for these peptides. In addition, results demonstrate that apart from direct LPS scavenging, membrane-localized peptide-induced LPS scavenging seem to contribute partially to anti-inflammatory effect. Furthermore, fragmentation and densification of LPS aggregates, in turn dependent on the peptide secondary structure on LPS binding, as well as aromatic packing interactions, correlate to the anti-inflammatory effect, thus promoting peptide-induced packing transition in LPS aggregates as key for anti-inflammatory functionality. Thus, peptide-induced LPS aggregate disruption together with reduction of the negative charge of LPS suggests the importance of phagocytosis as an alternative to the inflammatory pathway, which needs to be further investigated. Furthermore, PEG conjugation of peptide results in strongly reduced toxicity at a cost of reduced antimicrobial activity but markedly retained anti-inflammatory effect.

Taken together, the results obtained in this work have demonstrated several key issues which need to be taken into consideration in the development of effective and selective anti-inflammatory peptide therapeutics for the treatment of severe Gram-negative bacterial infections.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 64 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 216
LPS, Antimicrobial, Peptide, Inflammation, Infections, Liposome, Binding, PEG
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Physical Chemistry
urn:nbn:se:uu:diva-282781 (URN)978-91-554-9559-6 (ISBN)
Public defence
2016-06-03, B41, BMC, Husargatan 3, Uppsala, Uppsala, 09:15 (English)
Swedish Research Council
Available from: 2016-05-13 Created: 2016-04-06 Last updated: 2016-06-01

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Singh, ShaliniMalmsten, Martin
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