N-Arylpyrazole NOD2 Agonists Promote Immune Checkpoint Inhibitor Therapy

The characterization of microbiotamechanisms in healthand diseasehas reinvigorated pattern recognition receptors as prominent targetsfor immunotherapy. Notably, our recent studies on Enterococcus species revealed peptidoglycan remodeling and activation of NOD2as key mechanisms for microbiota enhancement of immune checkpointinhibitor therapy. Inspired by this work and other studies of NOD2activation, we performed in silico ligand screening and developed N-arylpyrazole dipeptides as novel NOD2 agonists. Importantly,our N-arylpyrazole NOD2 agonist is enantiomer-specificand effective at promoting immune checkpoint inhibitor therapy andrequires NOD2 for activity in vivo. Given the significant functionsof NOD2 in innate and adaptive immunity, these next-generation agonistsafford new therapeutic leads and adjuvants for a variety of NOD2-responsivediseases.