Indoleamine 2,3-dioxygenase 1 inhibitors: Molecular pharmacology, structural biology and medicinal chemistry with therapeutic perspectives for Huntington's disease.

Huntington's disease (HD) is an inherited, progressive neurodegenerative disorder caused by the expansion of the CAG repeat in the HTT (huntingtin) gene. Repeated CAG sequences in the HTT gene lead to the accumulation of a toxic form of the protein within cells that contain it. The kynurenine pathway (KP), which metabolizes the amino acid L-tryptophan, has been implicated in the pathology of HD. The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a primary component of the KP, producing several neuroactive metabolites, including the neurotoxic metabolite quinolinic acid (QA) and 3-hydroxykynurenine (3-HK). The activity of IDO1 is associated with inflammation, oxidative damage and excitotoxicity. Structures of IDO1 (as represented in the Protein Data Bank under PDB: 2D0T) have enabled the development of inhibitors, with Exiguamine A demonstrating potent IDO1 activity. Though there are challenges with IDO1 selectivity and its penetration into the brain, IDO1 remains a promising candidate and should be further evaluated as a therapeutic target in HD.