Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10836280 | Peptides | 2005 | 13 Pages |
Abstract
An original representative of the patented by author family of histamine-containing peptidomimetics l-glutamyl-histamine (l-Glu-Hist) was synthesized and characterized as a biologically active compound with a role of cytokine mimic leading to cellular responses of improved specificity. The study assesses the ability of l-Glu-Hist to affect molecular modeling, modulate free radical activity and influence immune cell signaling. The energy-minimized 3D conformations of l-Glu-Hist derived from its chemical structure resulted in stabilization for Fe2+ chelating complexes. l-Glu-Hist accelerated the decrease of ferrous iron in the ferrous sulfate solution in a concentration-dependent mode and showed the ferroxidase-like activity at concentrations less than 3 mM in the phenanthroline assay, whereas in the concentration range 3-20 mM l-Glu-Hist restricted the availability of Fe2+ to phenanthroline due to binding of ferrous ions in chelating complexes. l-Glu-Hist showed stimulatory effect on phosphatidylcholine liposomal peroxidation (LPO) catalyzed by the superoxide anion radical (O2â)-generating system (Fe2+ + ascorbate) at low (less or about 1 mM) l-Glu-Hist concentrations and both revealed the inhibitory effect on LPO in this system of high (â¼10 mM) l-Glu-Hist concentration. The stimulation of LPO by l-Glu-Hist was related to the ability of peptidomimetic in small (â¼0.05 mM) concentrations to release O2â free radicals as determined by the superoxide dismutase-inhibitable cytochrome c reduction assay. O2â release by l-Glu-Hist might result from its ferroxidase-like activity, while inhibition of LPO by l-Glu-Hist was caused by its chelating activity to Fe2+ ions, prevention of free radical generation and lipid hydroperoxide-degrading ability of 5-20 mM l-Glu-Hist. l-Glu-Hist released O2â in concentrations which stimulated [3H]-thymidine incorporation into DNA and proliferation of mouse spleen lymphocytes and mononuclear cells from human blood. l-Glu-Hist modulates the ability of oxygen free radicals to act as signaling agents at low concentrations, influencing gene expression. The structural peptide-like analogues of l-Glu-Hist such as l-Glu-Trp, carcinine (β-alanylhistamine), but not l-Pro-Glu-Trp were active in stimulating thymidine incorporation and in inducing proliferation of mononuclear cells as compared to mitogen concanavalin A at doses 2.5-25.0 μg/ml. Our data provide evidence that l-Glu-Hist may act as a very fast, specific and sensitive trigger for lymphocyte proliferation and immunoregulation. The cited abilities and further obtained in vivo results make Immudilin® ((INCI: glutamylamidoethyl imidazole, aqueous solution), l-Glu-Hist) a useful immunoregulatory agent.
Keywords
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Biochemistry
Authors
Mark A. Babizhayev, Yuri A. Semiletov, Yuri A. Lul'kin, Natalia L. Sakina, Ekaterina L. Savel'yeva, Ludmila M. Alimbarova, Igor Ph. Barinskii,