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Tryptophan end-tagging for promoted lipopolysaccharide interactions and anti-inflammatory effects
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Bose Inst, Dept Biophys, India.
Lund Univ, Div Dermatol & Venereol, Sweden.;Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore..
Bose Inst, Dept Biophys, India..
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 212Article in journal (Refereed) Published
Abstract [en]

The objective of the present study is the investigation of possibilities for boosting peptide anti-inflammatory effects by tryptophan end-tagging, including identification of underlying mechanisms for this. In doing so, effects of tryptophan end-tagging of KYE21 (KYEITTIHNLFRKLTHRLFRR), a peptide derived from heparin co-factor II, on membrane and lipopolysaccharide (LPS) interactions were investigated by ellipsometry, NMR, fluorescence spectroscopy, and circular dichroism measurements. Through its N-terminal W stretch, WWWKYE21 displays higher membrane binding, liposome rupture, and bacterial killing than unmodified KYE21. Analogously, W-tagging promotes binding to E. coli LPS and to its endotoxic lipid A moiety. Furthermore, WWWKYE21 causes more stable peptide/LPS complexes than KYE21, as evidenced by detailed NMR studies, adopting a pronounced helical conformation, with a large hydrophobic surface at the N-terminus due to the presence of W-residues, and a flexible C-terminus due to presence of several positively charged arginine residues. Mirroring its increased affinity for LPS and lipid A, WWWKYE21 displays strongly increased anti-inflammatory effect due to a combination of direct lipid A binding, peptide-induced charge reversal of cell membranes for LPS scavenging, and peptide-induced fragmentation of LPS aggregates for improved phagocytosis. Importantly, potent anti-inflammatory effects were observed at low cell toxicity, demonstrated for both monocytes and erythrocytes.

Place, publisher, year, edition, pages
2017. Vol. 7, article id 212
National Category
Pharmaceutical Sciences
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URN: urn:nbn:se:uu:diva-329140DOI: 10.1038/s41598-017-00188-7ISI: 000404126200011PubMedID: 28303012OAI: oai:DiVA.org:uu-329140DiVA, id: diva2:1148016
Funder
Swedish Research Council, 2012-1842, 2012-1883Knut and Alice Wallenberg FoundationAvailable from: 2017-10-09 Created: 2017-10-09 Last updated: 2018-01-13Bibliographically approved

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