engleski

Novel methodology for the preparation of immunostimulating mannose derived desmuramyl peptides

Muropeptides are fragments of peptidoglycans, unique polymers that build up the cell wall of bacteria. They are used as immunostimulating compounds (adjuvants). Muramyl dipeptide (MDP), N-acetylmuramyl-L-alanyl-D-isoglutamine, is the smallest structural unit of peptidoglycans showing the immunostimulating activity. Numerous MDP analogues lacking the hydrophilic carbohydrate moiety (desmuramyl peptides) with different groups at C- and N-terminus of the L-Ala-D-isoGln moiety have been synthesized. We have designed and synthesized desmuramyl peptides with incorporated lipophilic adamantyl group and also their mannosylated derivatives. Attached mannose allows the targeting of cell surface receptors recognizing glycans on immune cells while adamantane group facilitates the anchoring of the peptidoglycan ‘cargo’ to the membrane. Synthesized desmuramyl peptides have been encapsulated into liposomes, vehicles often used for the target delivery. In these liposomal formulations adamantane group penetrates into the lipid bilayer while mannose is exposed at the liposome surface and can serve in targeting mannose receptors. Since mannose derived desmuramyl peptides show great biological potential, we have developed novel and improved methodology for their synthesis. Previously described procedure included stereoselective glycosylation reaction with benzylated mannose, while new method consists of stereospecific α-O-mannosylation using tetraacetylated mannopyranose. Besides stereospecificity this strategy has several other advantages such as higher yields, shorter reaction times, easier purification of products and possibilities for the preparation of prodrug formulations, even at larger scale (gram scale). Novel methodology will be presented on a synthesis of series of desmuramyl peptides.

mannose; desmuramyl peptides; immunostimulation

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