TDO is a promising new drug target for Parkinson’s disease. NTRC has identified a novel series of selective TDO inhibitors using NFK Green™, a proprietary assay technology for high-throughput screening of tryptophan catabolizing enzymes.
Tryptophan is an essential amino acid that is used for protein synthesis and the production of neurotransmitters that regulate behavior, such as serotonin and melatonin. TDO is constitutively expressed at high levels in the liver and regulates systemic tryptophan levels. Recently, TDO was identified as a metabolic regulator of age-related toxicity of α-synuclein in a Caenorhabditis elegans model . α-synuclein is mainly found at the tip of nerve cells, the neurons, where it plays a role in the release of neurotransmitters. α-synuclein is normally an unstructured protein. However, in several neuropathologies, including Parkinson’s disease, α-synuclein occurs in nerve cells as protein aggregates, so-called Lewy bodies. Furthermore, point mutations in the α-synuclein gene have been linked to familial forms of Parkinson’s disease. Depletion of TDO in the worm model also suppressed the toxicity of amyloid-β and poly-glutamine, proteins involved in Alzheimer’s and Huntington’s disease, and increased lifespan . The same effect could be obtained by addition of dietary L-tryptophan. These studies support the idea that restoring the balance in tryptophan metabolism may provide therapeutic benefit in patients with neurodegenerative disease.
NTRC scientists have developed a new and innovative screening assay for TDO, NFK Green™, and have applied this assay for ultra-high throughput screening at the Pivot Park Screening Centre. A lead optimization program, which was supported by the Michael J. Fox Foundation, resulted in TDO inhibitors with potent activity in biochemical and cellular assays, and selectivity over IDO1. The inhibitors are currently used in a collaboration with Utrecht University to validate TDO as a potential therapeutic target for Parkinson’s disease in in vivo models of neurodegenerative disease.
If you are interested to learn more about this project, contact us.
Publications of NTRC and collaborators on TDO
 Van der Goot et al. (2012) Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. Proceedings of the National Academy of Sciences USA 109, 14912-14917.
 Michels et al. (2016) Identification of an evolutionary conserved structural loop that is required for the enzymatic and biological function of tryptophan 2,3-dioxygenase. Scientific Reports 6: 39199.