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: Praveen Papareddy, Martina Kalle, Shalini Singh, Matthias Mörgelin, Artur Schmidtchen, Martin Malmsten
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1838 Issue 5 Pg. 1225-34 (May 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24522010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Antimicrobial Cationic Peptides
• Cytokines
• Endotoxins
• Lipids
• Lipopolysaccharides
• Heparin Cofactor II

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antimicrobial Cationic Peptides (pharmacology)
• Bacteria (drug effects, metabolism)
• Cell Line
• Cell Membrane (drug effects)
• Cytokines (metabolism)
• Endotoxins (antagonists & inhibitors)
• Heparin Cofactor II (pharmacology)
• Humans
• Inflammation (drug therapy, metabolism)
• Lipids
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Protein Structure, Tertiary
• Shock, Septic (drug therapy, metabolism)