Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase.

Abstract

Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50 value of 0.88 μM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 Å resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood-brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS.

• Authors: Zehui Liu, Qian Hu, Wanyan Wang, Sisi Lu, Dang Wu, Shuyin Ze, Jiacheng He, Ying Huang, Wuyan Chen, Yechun Xu, Weiqiang Lu, Jin Huang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 177 Pg. 114000 (07 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32353424 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Alkaloids
• Benzodioxoles
• Biological Products
• Dihydroorotate Dehydrogenase
• Enzyme Inhibitors
• Myelin-Oligodendrocyte Glycoprotein
• Peptide Fragments
• Piperidines
• Polyunsaturated Alkamides
• myelin oligodendrocyte glycoprotein (35-55)
• Oxidoreductases Acting on CH-CH Group Donors
• piperine

Topics

• Alkaloids (chemistry, metabolism, pharmacology)
• Animals
• Benzodioxoles (chemistry, metabolism, pharmacology)
• Biological Products (pharmacology)
• Blood-Brain Barrier (drug effects)
• Crystallography, X-Ray
• Dihydroorotate Dehydrogenase
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, drug therapy, pathology)
• Enzyme Inhibitors (chemistry, metabolism, pharmacology)
• Female
• Humans
• Jurkat Cells
• Mice, Inbred C57BL
• Models, Molecular
• Molecular Targeted Therapy
• Myelin Sheath (metabolism)
• Myelin-Oligodendrocyte Glycoprotein (toxicity)
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, chemistry, genetics, metabolism)
• Peptide Fragments (toxicity)
• Piperidines (chemistry, metabolism, pharmacology)
• Polyunsaturated Alkamides (chemistry, metabolism, pharmacology)
• Spleen (cytology)