Wednesday, March 12, 2025
3/12/2025
Neurodegenerative disease is an emerging public health crisis with Alzheimer’s disease (AD) being the 6th leading cause of death that affects 6.7M patients in the US alone. To date, no curative agents have been identified, and commonly prescribed therapeutics (donepezil, memantine) remediate symptoms, but are wholly ineffective at treating the underlying condition. Contemporary literature suggests that the build-up of neurotoxic kynurenine pathway (KP) metabolites might promote AD pathogenesis. One such neurotoxic KP metabolite, quinolinic acid (QUIN), agonizes the N-methyl-D-aspartate (NMDA) receptor and exerts broad-spectrum neurotoxicity, particularly in the hippocampus and striatum. Notably, neurodegeneration of the hippocampus is a hallmark of AD dementia. As such, regulation of QUIN biosynthesis offers an attractive approach to the treatment of AD. In the proposed research, we aim to regulate QUIN biosynthesis within the CNS by targeting the tryptophan 2,3-dioxygenase enzyme (TDO). TDO is a tetrameric heme-dependent enzyme responsible for the rate-determining first step of the KP. Rather than target the heme-dependent TDO active site, we aim to target a non-catalytic binding site that plays a critical role in the stability of the active tetramer. The central hypothesis of the proposed research is that small molecule-mediated destabilization of this non-catalytic site constitutes a novel approach to the regulation of neurotoxic KP metabolites, and thus a novel approach to the treatment of AD. We will test this hypothesis through two complementary aims. Aim 1 will utilize computational modeling and chemical synthesis to deliver non-catalytic site-selective small molecule degraders of TDO. Aim 2 will assess the therapeutic viability of compounds generated in aim 1 through a series of biochemical assays. Specifically, the TDO degrading effects of each compound will be measured via an ELISA assay, quantitative KP metabolite profiling, and isothermal calorimetry. The pharmacokinetic profiles of select compounds will be assessed via MDCK and microsomal stability assays. Together, these aims will deliver CNS-penetrant TDO degraders and characterize their pharmacological effects on the propagation of neurotoxic KP metabolites. The ligands identified could serve as valuable tool compounds for follow-up studies in translational neuroscience to interrogate the role of KP metabolites in AD pathogenesis.
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