3D molecular modeling, free radical modulating and immune cells signaling activities of the novel peptidomimetic l-glutamyl-histamine: possible immunostimulating role
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 as...
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| Published in: | Peptides (New York, N.Y. : 1980) Vol. 26; no. 4; pp. 551 - 563 |
|---|---|
| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
New York, NY
Elsevier Inc
01-04-2005
Elsevier Science |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | 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 Fe
2+ 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 Fe
2+ 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 (O
2
−
)-generating system (Fe
2+
+
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 (∼10
mM)
l-Glu-Hist concentration. The stimulation of LPO by
l-Glu-Hist was related to the ability of peptidomimetic in small (∼0.05
mM) concentrations to release O
2
−
free radicals as determined by the superoxide dismutase-inhibitable cytochrome
c reduction assay. O
2
−
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 Fe
2+ ions, prevention of free radical generation and lipid hydroperoxide-degrading ability of 5–20
mM
l-Glu-Hist.
l-Glu-Hist released O
2
−
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. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0196-9781 1873-5169 |
| DOI: | 10.1016/j.peptides.2004.11.012 |