NOD2 (nucleotide-binding oligomerization domain 2) is an intracellular pattern recognition receptor. NOD2 is one of cytoplasmic PRRs, and antigen-presenting cells and certain mucosal epithelia primarily express it. It assembles with RIP-2 kinase in response to the presence of bacterial muramyl dipeptide (MDP) in the host cell cytoplasm. Thereby, it induces signals leading to the production of pro-inflammatory cytokines. Various inflammatory disorders show association with dysregulation of NOD2 signaling. Thus, NOD2 is a potential target for therapeutic intervention. In this study, GSK717 is a potent, selective NOD2 inhibitor. GSK717 inhibits muramyl dipeptide (MDP)-induced NOD2-mediated signaling. In addition, it has an IC50 of 400 nM for MDP-stimulated IL-8 secretion in HEK293/hNOD2 cells.
NOD2 may undergo a conformational change upon binding the bacterial cell wall component muramyl dipeptide (MDP) to enable ATP binding, oligomerization, and recruitment of the serine/threonine kinase RIP2. In turn, this leads to the recruitment of additional effector kinases including TAK1/TAB1 and the formation of a poly-ubiquitinated signaling complex that stimulates canonical NF-κB and MAPK (p38, JNK) pathways. Thereby, it leads to increased synthesis of pro-inflammatory cytokines and chemokines. In addition, NOD2 increases inflammatory cytokine production by macrophages and dendritic cells synergistically with several members of the toll-like receptor (TLR) family of membrane-associated PRRs. Fortunately, GSK717 also blocks synergy between NOD2 and TLR2. Moreover, GSK717 does not affect NOD1, TNFR1, and TLR2-mediated responses. Furthermore, GSK717 (5 μM) inhibits the release of IL-8, IL-6, TNFα, and IL-1β in primary human monocytes stimulated with MDP.
In summary, GSK717 is a potent, selective NOD2 inhibitor, and it has the potential to investigate the importance of NOD2 in various inflammatory processes and may have potential clinical utility.
Rickard DJ, et al. PLoS One. 2013;8(8):e69619. Published 2013 Aug 1.