Ultrashort cationic lipopeptides and lipopeptoids selectively induce cytokine production in macrophages

PLoS One. 2013;8(2):e54280. doi: 10.1371/journal.pone.0054280. Epub 2013 Feb 4.


A series of ultrashort lipopeptides and lipopeptoids were tested for their ability to induce cytokine production in macrophages. Fourteen compounds were found to strongly induce production of chemokines Groα and IL-8, with a structural bias that was absent from previous antibacterial activity investigations. Compounds based on LysGlyLys and NLysGlyNLys sequences did not induce cytokine production, whereas those based on LysLysLys and NLysNLysNLys were active only when linked to a lipid tail at least sixteen carbons long. Three lipopeptides induced high levels of IL-8 production, above that of equivalent concentrations of cathelicidin LL-37, while no compound induced production of the pro-inflammatory cytokine TNF-α at or below 100 µM. Two compounds, peptoids C16OH-NLysNLysNLys and C16OH-NHarNHarNHar, were selective for IL-8 production and did not induce TNF-α or IL-1β. These compounds may prove beneficial for in vivo treatment of infectious disease, with improved bioavailability over LL-37 due to their protease-resistant scaffold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimicrobial Cationic Peptides / biosynthesis*
  • Antimicrobial Cationic Peptides / metabolism
  • Cell Differentiation
  • Cell Line
  • Chemokine CXCL1 / biosynthesis*
  • Chemokine CXCL1 / metabolism
  • Humans
  • Interleukin-1beta / deficiency
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / metabolism
  • Lipopeptides / chemical synthesis
  • Lipopeptides / chemistry*
  • Lipopeptides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Molecular Structure
  • Monocytes / cytology
  • Peptoids / chemical synthesis
  • Peptoids / chemistry*
  • Peptoids / pharmacology
  • Protein Stability
  • Structure-Activity Relationship
  • Surface-Active Agents / chemical synthesis
  • Surface-Active Agents / chemistry*
  • Surface-Active Agents / pharmacology
  • Tumor Necrosis Factor-alpha / deficiency


  • Antimicrobial Cationic Peptides
  • Chemokine CXCL1
  • Interleukin-1beta
  • Interleukin-8
  • Lipopeptides
  • Peptoids
  • Surface-Active Agents
  • Tumor Necrosis Factor-alpha
  • CAP18 lipopolysaccharide-binding protein

Grant support

This research was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canadian Foundation for Innovation (CFI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.