Screening Of Novel Efficient IDO Inhibitors And Its Mechanism

Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism ultimately leads to the production of the L-kynurenine and quinolinic acid (QUIN). IDO has recently been established as one of the key players involved in the pathogenesis of AD and tumor immune escapse. Many experiments have provided proof-of-principle demonstrations of the potential value of IDO inhibitors in cancer treatment. A well-known traditional Chinese medicinal prescription, Oren-gedoku-to (OGT), has been used in clinical therapies for many types of dementia in China and Japan. OGT is indicated to prevent cholinergic dysfunction and reduce oxidative stress; however, the exact mechanism underlying its ability to improve cognitive ability remains elusive.4-Aryl-1,2,3-triazoles have widespread applications in pharmaceuticals and agrochemicals. Here we presented a novel mechanism of OGT’s therapeutic potential in AD. We demonstrated that OGT significantly inhibited recombinant human IDO (rhIDO) activity in vitro, and its four main constituents (i.e., berberine, palmatine, jatrorrhizine and baicalein) were potent IDO inhibitors. Three derivatives 4,14,15 of 1,2,3-Triazoles exhibited potent IDO inhibitory activity. The IC50 values of them obtained from a cell-based assay of HEK 293 cells and an enzymatic assay were much lower than that of the most commonly used IDO inhibitor,1-methyl tryptophan (1-MT). Compound 4,14,15 enhanced the proliferation of T cells stimulated with LLC tumor cells in a dose-dependent effect. Our work provides a new angle in understanding pathology of AD and may has found several lead compounds for drug development of IDO inhibitors...