KEY RESULTS
Piperine was identified as a natural inhibitor of human DHODH with an IC50 value of 0.88 ± 0.04 μM. In addition, we resolved the co-complex crystal structure of DHODH and piperine at 1.98 Å resolution and found that Tyr356 residue of DHODH is critical for piperine binding. Moreover, piperine can markedly suppress T cell overactivation via a DHODH dependent-manner. Finally, we found that piperine exhibits strong preventive and therapeutic effect in the MOG-induced EAE by restricting inflammatory cells infiltration into the CNS and by preventing myelin destruction and blood–brain barrier (BBB) disruption.