engleski

Synthesis and conformational study of desmuramyl di-, tri- and tetrapeptides

Muramyldipeptide (MDP), N-acetylmuramyl-L- alanyl-D-isoglutamine, is the smallest structural unit of peptidoglycans displaying immunostimulating (adjuvant) activity. Structure-activity relationship studies of muropeptides suggest that the desmuramyl dipeptide part (L-Ala-D-isoGln) is responsible for the adjuvant activity [1]. Primary structure modifications as well as their conformational changes may be responsible for changes in biological activity of peptides. Increase of lipophilicity in the N- and C- terminus of the dipeptide, such as introduced adamantly group at the N- terminal amino acid, can significantly improve pharmacological properties of desmuramyl peptides. Synthesis as well as conformational computational and experimental NMR analysis of corresponding desmuramyl dipeptide, tripeptide and tetrapeptide derivatives in zwitterionic and non-zwitterionic form was performed. L-Alanyl-D-isoglutamine was obtained by the removal of N- and C- protecting groups from commercially available dipeptide. Tri- and tetrapeptides were obtained by consecutive attachment of corresponding amino acids (1-adamantyl-glycine and serine) to desmuramyl dipeptide, using optimized coupling methodology (EDC/HOBt coupling reagents in the mixture of solvents CH2Cl2/1, 4- dioxane 1:1). (S)-1- adamantyl-glycyl-L-alanyl-D-isoglutamine was prepared in four synthetic steps using more efficient method than previously reported [2, 3]. The most stable conformers of synthesized peptides were determined. A systematic conformational space search was performed by means of molecular and quantum mechanical study in solution, which was modelled as a polarizable continuum. Hydrogen bonds were determined by using the QTAIM population analysis method. Calculated conformers were compared with those obtained in solution by NMR study in deuterated water and DMSO.

desmuramyl peptides ; conformational study ; adjuvants

We wish to thank the Croatian Science Foundation for support (project IP-2014-09-7899).