The effect of chemical structure and stereochemistry on interactions of immunomodulatory peptides with lipid bilayers in liposomes

摘要

Adjuvants are compounds that are used to enhance the immune response of the host to an antigen.Among others the peptidoglycan fragments were recognized as potent immunomodulators.Our studies concern the peptidoglycan monomer,GlcNAc-MurNAc-L-Ala-D-isoGlnmesoDAP(omega NH_2)-D-Ala-D-Ala(PGM),the natural compound originating from the Brevibacterium divaricatum peptidoglycan,its semisynthetic derivatives(Boc-Tyr-PGM and(Adamant-l-yl)-acetyl-PGM)and synthetic adamantyltripeptides D-and L-(adamant-2-yl)-Gly-L-Ala-D-isoGrn(AdTP1 and AdTP2)(Figure 1).Biological activity of the prepared compounds has been continuously investigated and reported.In order to slow down their hydrolytic inactivation and thus achieve a prolonged biological action they were incorporated into liposomes.The interactions of incorporated compounds with lipids in liposomal bilayers were investigated by Electron Spin Resonance(ESR)spectroscopy.The fatty acids bearing the nitroxide moiety at different positions along the acyl chain(n = 7,10,16)were used to investigate the interaction of tested compounds with negatively charged multilamellar liposomes(eggPC:CHL:DCPH=7:5:l).At first the ESR study included the investigation of the interaction of PGM and diastereoisomers of adamantyltripeptides with phospholipids in liposomal bilayers.The results showed that adamantyltripeptides affected the motional properties of all spin labelled lipids,while the entrapment of PGM had no effect.Comparative study of the conformations of the synthetically modified derivatives(Adamant-1-yl)-acetyl-PGM and Boc-Tyr-PGM with respect to the unsubstituted PGM using NMR spectroscopy and molecular modelling revealed that the lipophilic substituents attached to the amino group of the diaminopimelic acid introduce changes to the conformational preferences of the peptide moiety.The study of possible interaction with liposomal membrane is relevant to the use of the tested compounds incorporated into liposomes,as adjuvants in vivo.