bc8b00763_si_001.pdf (175.42 kB)
Conjugate of Enkephalin and Temporin Peptides as a Novel Therapeutic Agent for Sepsis
journal contribution
posted on 2018-12-10, 19:37 authored by A. Golda, P. Kosikowska-Adamus, O. Babyak, M. Lech, M. Wysocka, A. Lesner, J. Potempa, J. KozielAntimicrobial peptides (AMPs) exhibit
a wide spectrum of actions,
ranging from a direct bactericidal effect to multifunctional activities
as immune effector molecules. The aim of this study was to examine
the anti-inflammatory properties of a DAL-PEG-DK5 conjugate composed
of a lysine-rich derivative of amphibian temporin-1CEb (DK5) and dalargin
(DAL), the synthetic Leu-enkephalin analogue. Detailed study of the
endotoxin-neutralizing activity of the peptide revealed that DAL-PEG-DK5
interacts with LPS and the LPS binding protein (LBP). Moreover, DAL-PEG-DK5
prevented dimerization of TLR4 at the macrophage surface upon LPS
stimulation. This inhibited activation of the NF-κB signaling
pathway and markedly reduced pro-inflammatory cytokine production.
Finally, we showed that aggregation of DAL-PEG-DK5 into amyloid-like
structures induced by LPS neutralized the endotoxin proinflammatory
activity. Consequently, DAL-PEG-DK5 reduced morbidity and mortality in vivo, in a mouse model of endotoxin-induced septic shock.
Collectively, the data suggest that DAL-PEG-DK5 is a promising therapeutic
compound for sepsis.