title: An antimicrobial helix A-derived peptide of heparin cofactor II blocks endotoxin responses in vivo.
abstract: Host defense peptides are key components of the innate immune system, providing multi-facetted responses to invading pathogens. Here, we describe that the peptide GKS26 (GKSRIQRLNILNAKFAFNLYRVLKDQ), corresponding to the A domain of heparin cofactor II (HCII), ameliorates experimental septic shock. The peptide displays antimicrobial effects through direct membrane disruption, also at physiological salt concentration and in the presence of plasma and serum. Biophysical investigations of model lipid membranes showed the antimicrobial action of GKS26 to be mirrored by peptide incorporation into, and disordering of, bacterial lipid membranes. GKS26 furthermore binds extensively to bacterial lipopolysaccharide (LPS), as well as its endotoxic lipid A moiety, and displays potent anti-inflammatory effects, both in vitro and in vivo. Thus, for mice challenged with ip injection of LPS, GKS26 suppresses pro-inflammatory cytokines, reduces vascular leakage and infiltration in lung tissue, and normalizes coagulation. Together, these findings suggest that GKS26 may be of interest for further investigations as therapeutic against severe infections and septic shock.
authors: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden.
authors: Praveen
authors: P
authors: Papareddy
authors: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden.
authors: Martina
authors: M
authors: Kalle
authors: Department of Pharmacy, Uppsala University, SE-75123 Uppsala, Sweden.
authors: Shalini
authors: S
authors: Singh
authors: Division of Infection Medicine, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden.
authors: Matthias
authors: M
authors: Mörgelin
authors: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, 308232, Singapore.
authors: Artur
authors: A
authors: Schmidtchen
authors: Department of Pharmacy, Uppsala University, SE-75123 Uppsala, Sweden. Electronic address: martin.malmsten@farmaci.uu.se.
authors: Martin
authors: M
authors: Malmsten
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D015844:Heparin Cofactor II / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008055:Lipids; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D004731:Endotoxins; D008055:Lipids; D008070:Lipopolysaccharides; D015844:Heparin Cofactor II
keywords: Antimicrobial peptide; Lipid A; Lipopolysaccharide; Membrane