engleski

Structural Acpects and Biological Evaluation of New Mannose Derived Immunomodulating Adamantyltripeptides

The aim of this study was to synthesize, characterize and investigate the influence of mannose derived adamantyltripeptides on humoral immune reaction in mice. The adamantyltripeptides are chemically characterized compounds and in our previous investigations we have demonstrated their different biological activity, especially adjuvanticity. Also, it is well known that glycosylation affects several cell functions such as proliferation and differentiation and also the immune response in mammals. It is well documented that mannose receptors are present on the cell surface of macrophages and other immunocompetent cells. D-Mannose was coupled to D/L-(adamant-1-yl)Gly-L-Ala-D-isoGln (Ad1TP1 and Ad1TP2) and D/L-(adamant-2-yl)Gly-L-Ala-D-isoGln (Ad2TP1 and Ad2TP2) via chiral linker (HOCH2CH(CH3)COOCH3), and the resulted several diastereoisomers obtained were characterized by NMR and their purity was tested by HPLC. All the examined compounds are water-soluble, non-toxic and non-pyrogenic substances. Their adjuvant effect was tested on CBA mice with ovalbumin as a model antigen. The results revealed that the adjuvant activity of examined compounds was changed in comparison to the parent adamantyltripeptide molecules. The statistically significant difference in induction of total specific IgG antibodies was found for the D-(adamant-1-yl)Gly-L-Ala-D-isoGln and D-Man-OCH2CH(CH3)CO-D-(adamant-1-yl)Gly-L-Ala-D-isoGln, respectively, when the chiral carbon atom in the linker molecule had the R absolute configuration. Also, the significant difference was observed between two examined molecules of mannose-adamantyltripeptides regarding the R and S absolute configuration on chiral carbon atom in the linker molecule. The analyses of specific IgG subclasses IgG1 and IgG2a revealed the influence of mannose derived adamantyltripeptides on Th1 and Th2 type of immune reaction. OVA given without adjuvants induced IgG1 predominantly, reflecting the induction of Th2 immune response. The effects of examined compounds on IgG1 induction were basically the same as those observed for total specific IgG. Regarding IgG2a, the significant difference was again found between mannose-adamantyltripeptides coupled by R and S linker, respectively. From all examined compounds only mannose-Ad1TP2 with S linker had significant impact on switching the immune response towards more pronounced Th2 response specific for OVA. However, the immune response to each compound will be discussed in detail.

immunomodulating peptides; adjuvants; adamantyltripeptides; mannose

nije evidentirano