A Robust, Gram-Scale and High-Yield Synthesis of MDP Congeners for Activation of the NOD2 Receptor and Vaccine Adjuvantation

Abstract

Bacterial peptidoglycan (PGN) constituent – muramyl dipeptide (MDP) and its congeners possess immuno-adjuvant activity, and find their applications in vaccines to potentiate the immune response of antigens. The molecule confers non-specific resistance to pathogenic infections and defense against tumors. In this work, the parent MDP molecule was re-designed by replacing its carbohydrate moiety with an immunoregulatory xanthine scaffold, while conserving L-D configuration of the pharmacophore. Alkyl chains were introduced at the C-terminus of D-isoglutamine to help the molecules access cytoplasmic NOD2 receptor and activate the innate immune system. Lipophilic MDP congeners were thus obtained by adopting a direct or indirect convergent synthetic route with an overall yield of > 50 %. We found that an indirect approach can be reliably implemented on a gram-scale, thereby unlocking access to substantial amounts of pathogen associated molecular patterns for in vivo studies, which will accelerate the development of NOD2 immuno-adjuvants against viral and bacterial infections.