Improved Synthesis of D‐Isoglutamine: Rapid Access to Desmuramyl Analogues of Muramyl Dipeptide for the Activation of Intracellular NOD2 Receptor and Vaccine Adjuvant Applications

다국어 초록 (Multilingual Abstract)

Muramyl dipeptide (MDP) – the smallest immunomodulatory unit of bacterial peptidoglycan – has adjuvant activity and triggers the innate immune system against bacterial and viral infections. The inherited drawbacks of MDP, such as pyrogenicity and poor macrophage penetration, can be resolved by structural modifications, thereby improving its pharmacological profile and adjuvant activity. Herein, several desmuramyl analogues of MDP were designed by replacing the carbohydrate fragment (MurNAc) of the parent molecule with an immunomodulatory xanthine scaffold. The L−D configurations of the pharmacophoric dipeptidyl moiety were conserved and alkyl chains of moderate length were introduced at isoglutamine to enhance their cellular uptake. The synthesis of these analogues features a novel synthetic route for D‐isoglutamine fragment with an overall yield of >50 % in ten to eleven steps. This sufficiently flexible approach provides rapid access to desmuramyl analogues of MDP on a gram scale, which can help accelerate the development of novel NOD2 agonists and immunoadjuvants.
Bacterial peptidoglycan subunit – muramyl dipeptide (MDP) – activates the innate immune system through the NOD2 receptor. Lipophilic desmuramyl analogues of MDP were synthesized by using a remarkably simple and scalable method, which involves a new strategy for the preparation of d‐isoglutamine fragment of pharmacophoric dipeptidyl moiety. This new approach will help accelerate the development of new immunoadjuvants against bacterial and viral infections.