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2‐Amino Muramyl Dipeptide Derivatives: Chemical probes to assay the stability and activation of NOD2

Mutations of the cytosolic protein nucleotide‐binding oligomerization domain‐containing protein 2 (NOD2), which detects the synthetic bacterial cell wall fragment muramyl dipeptide (MDP), are implicated in making individuals more susceptible to Crohn's disease (CD). However, the mode by which these mutations affect the pathogenesis of this disease is not fully understood. Interestingly, studies suggest NOD2 positively and negatively regulates the expression of toll‐like receptors (TLRs) and the consequent production of inflammatory molecules upon activation. Like NOD2, TLRs can detect bacterial fragments and produce an inflammatory response via the NF‐kB pathway, though through distinct mechanisms. Stabilizing the NOD2 Crohn's mutants through protein‐ligand binding can be a potential therapeutic target for CD. A library of MDP derivatives with altering functionality at the 2‐amino position were synthesized in order to investigate the stabilization imparted to NOD2 upon binding. A simplified 7‐step synthetic route to prepare 2‐amino MDP and subsequent functionalization of the molecule with mild NHS coupling or acetylating conditions is utilized. Compounds are then tested for stabilization with the cellular thermal shift assay (CESTA). In this cell‐based assay, binding of a ligand to a protein stabilizes a protein and protects it against thermal degradation at increased temperatures, resulting in a thermal shift (ΔTm) when compared to the unbound protein. The activation of the NF‐kB pathway by these molecules is tested concurrently, using a luciferase reporter assay to determine if changes in functionalization also yield a modulated immune response.