title: 3D molecular modeling, free radical modulating and immune cells signaling activities of the novel peptidomimetic L-glutamyl-histamine: possible immunostimulating role.
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 (O2*-)-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 (approximately 10 mM) L-Glu-Hist concentration. The stimulation of LPO by L-Glu-Hist was related to the ability of peptidomimetic in small (approximately 0.05 mM) concentrations to release O2*- free radicals as determined by the superoxide dismutase-inhibitable cytochrome c reduction assay. O2*- 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 O2*- 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 (beta-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 microg/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.
authors.affiliation: Innovative Vision Products Inc., Delaware, USA. markbabizhayev2004@yahoo.com
authors.forename: Mark A
authors.initials: MA
authors.lastname: Babizhayev
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Semiletov
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Lul'kin
authors.forename: Natalia L
authors.initials: NL
authors.lastname: Sakina
authors.forename: Ekaterina L
authors.initials: EL
authors.lastname: Savel'yeva
authors.forename: Ludmila M
authors.initials: LM
authors.lastname: Alimbarova
authors.forename: Igor Ph
authors.initials: IP
authors.lastname: Barinskii
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002614:Chelating Agents; D045304:Cytochromes c / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology; D013481:Superoxides
chemical_list: D000276:Adjuvants, Immunologic; D002614:Chelating Agents; D004151:Dipeptides; D009842:Oligopeptides; C120432:glutamyl-histamine; D013481:Superoxides; D045304:Cytochromes c