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Current research describing the role of IDO and its mechanism of action suggests that the inhibition of IDO with small molecule inhibitors, especially in conjunction with chemotherapy, can provide an effective and novel treatment strategy. When the connections between IDO and immune tolerance were first being realized in the late 1990s and 2000s, the search for potent and biocompatible inhibitors became an attractive area of research. Among the first IDO inhibitors were the betacarbolines and tryptophan analogues. Other research groups, like Andersen and co-workers, went looking to nature in their quest for IDO inhibitors. In 2006, while searching for a new structural class of IDO inhibitors from marine sponge isolates, Anderson’s group discovered exiguamine A and annulin B to be potent inhibitors, with Ki= 210 nM and 120nM, respectively. As their search continued, they discovered that the plectosphaeroic acids A-C, produced from marine fungus Plectosphaerella cucumerina, also showed potency against IDO (IC50 =2µM). Four years later, Overman’s group contributed to the development of natural product-based IDO inhibitors by completing the first total syntheses of the structurally unique plectosphaeroic acids B and C to allow for further (structure-activity relationship) SAR studies. In 2010, Thomas and co-workers reported the seleniumcontaining drug called ebselen was found to be a potent IDO inhibitor with an IC50 of 94nM. Their studies indicated that ebselen inhibits IDO by reacting with the cysteine residues (likely though the selenium atom), causing a change in protein conformation and the active-site heme, which lead to an increase in non-productive substrate binding. Ebselen was also found to have low toxicity and is being investigated as a treatment for a variety of other conditions including hearing loss, stroke and bipolar disorder. Notably, these examples serve to illustrate the broad variety of structures that have been reported as IDO inhibitors.