engleski

Synthesis of immunostimulating mannosylated desmuramyl peptides and a structural insights into NOD2 binding

Muramyl dipeptide (MDP, N-acetylmuramyl-L-alanyl- D-isoglutamine) is the smallest peptidoglycan fragment with adjuvant activity. MDP acts as a pathogen-associated molecular pattern and activates the NOD2 receptor. We have designed and prepared MDP analogs, desmuramyl peptides containing lypophilic 2-aminoadamantane-2- carboxylic acid, and furthermore modified it with mannose moieties. Here we present the design and synthesis of desmuramyl peptides containing 2- aminoadamantane-2-carboxylic acid, and its mono- and di-mannosylated derivatives. They exhibited an improved immunological activity in vivo in the mouse model, and the di-mannoslyated derivative showed to be the most active one. Therefore, molecular-dynamic simulations of NOD2 receptor complexes and manosylated desmuramyl peptides were performed. The intact structure of the NOD2 protein with seven loops, which were omitted in the experimentally solved structure, was modeled and the binding of synthesized mannose mimetics of MDP to NOD2 was investigated. Two potential binding sites have been identified, one located within the NBD domain and the other on the concave portion of the LRR surface of the NOD2 domain.

mannosylated desmuramyl peptides, NOD2 receptor, immunostimulation

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