The Synthetic Antimicrobial Peptide 19-2.5 Interacts with Heparanase and Heparan Sulfate in Murine and Human Sepsis.

Abstract

Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains from their proteoglycans. Thereby, heparanase liberates highly potent circulating heparan sulfate-fragments (HS-fragments) and triggers the fatal and excessive inflammatory response in sepsis. As a potential anti-inflammatory agent for sepsis therapy, peptide 19-2.5 belongs to the class of synthetic anti-lipopolysaccharide peptides; however, its activity is not restricted to Gram-negative bacterial infection. We hypothesized that peptide 19-2.5 interacts with heparanase and/or HS, thereby reducing the levels of circulating HS-fragments in murine and human sepsis. Our data indicate that the treatment of septic mice with peptide 19-2.5 compared to untreated control animals lowers levels of plasma heparanase and circulating HS-fragments and reduces heparanase activity. Additionally, mRNA levels of heparanase in heart, liver, lung, kidney and spleen are downregulated in septic mice treated with peptide 19-2.5 compared to untreated control animals. In humans, plasma heparanase level and activity are elevated in septic shock. The ex vivo addition of peptide 19-2.5 to plasma of septic shock patients decreases heparanase activity but not heparanase level. Isothermal titration calorimetry revealed a strong exothermic reaction between peptide 19-2.5 and heparanase and HS-fragments. However, a saturation character has been identified only in the peptide 19-2.5 and HS interaction. In conclusion, the findings of our current study indicate that peptide 19-2.5 interacts with heparanase, which is elevated in murine and human sepsis and consecutively attenuates the generation of circulating HS-fragments in systemic inflammation. Thus, peptide 19-2.5 seems to be a potential anti-inflammatory agent in sepsis.

• Authors: Lukas Martin, Rebecca De Santis, Patrick Koczera, Nadine Simons, Hajo Haase, Lena Heinbockel, Klaus Brandenburg, Gernot Marx, Tobias Schuerholz
• Journal: PloS one (PLoS One) Vol. 10 Issue 11 Pg. e0143583 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26600070 (Publication Type: Journal Article)

Chemical References

• Anti-Infective Agents
• Peptides
• Heparitin Sulfate
• heparanase
• Glucuronidase

Topics

• Adult
• Animals
• Anti-Infective Agents (chemical synthesis, therapeutic use)
• Enzyme-Linked Immunosorbent Assay
• Glucuronidase (metabolism)
• Heparitin Sulfate (metabolism)
• Humans
• Mice
• Peptides (chemical synthesis, therapeutic use)
• Sepsis (drug therapy, enzymology, metabolism)