title: Lipidated α-peptide/β-peptoid hybrids with potent anti-inflammatory activity.
abstract: In this study, we investigated, optimized, and characterized a novel subclass of host defense peptide (HDP) mimics based on α-peptide/β-peptoid hybrid oligomers with an alternating cationic/hydrophobic design with respect to their ability to modulate the pro-inflammatory response by human primary leukocytes upon exposure to bacterial components. Structure-activity studies revealed that certain lipidated α-peptide/β-peptoid hybrid oligomers possess anti-inflammatory activities in the submicromolar range with low cytotoxicity, and that the anti-inflammatory activity of the HDP mimics is dependent on the length and position of the lipid element(s). The resulting lead compound, Pam-(Lys-βNSpe)6-NH2, blocks LPS-induced cytokine secretion with a potency comparable to that of polymyxin B. The mode of action of this HDP mimic appears not to involve direct LPS interaction since it, in contrast to polymyxin B, displayed only minor activity in the Limulus amebocyte lysate assay. Flow cytometry data showed specific interaction of a fluorophore-labeled lipidated α-peptide/β-peptoid hybrid with monocytes and granulocytes indicating a cellular target expressed by these leukocyte subsets.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Skovbakke
authors.forename: Camilla J
authors.initials: CJ
authors.lastname: Larsen
authors.forename: Peter M H
authors.initials: PM
authors.lastname: Heegaard
authors.forename: Lise
authors.initials: L
authors.lastname: Moesby
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D057786:Peptidomimetics / Q000494:pharmacology*; D034444:Peptoids / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D007155:Immunologic Factors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D057786:Peptidomimetics; D034444:Peptoids; D014409:Tumor Necrosis Factor-alpha