Small Molecule Degraders of Tryptophan 2,3-Dioxygenase Enzyme (TDO) as Novel Treatments for Neurodegenerative Disease

色氨酸 2,3-双加氧酶 (TDO) 的小分子降解剂作为神经退行性疾病的新疗法

• 批准号: 10752555
• 负责人: Trevor Trombley
• 金额: $ 4.77万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752555
• 关键词: Accounting; Active Learning; Active Sites; Affect; Affinity; Agonist; Alzheimer' s Disease; Anabolism; Binding; Binding Sites; Biochemical; Biological Assay; Calorimetry; Catabolism; Cause of Death; Cellular Assay; Central Nervous System; Clinical Trials; Complex; Computer Assisted; Computer Models; Corpus striatum structure; Cytochrome P450; Databases; Dementia; Disease; Drug Design; Drug Kinetics; Enzyme Inhibition; Enzyme-Linked Immunosorbent Assay; Enzymes; Event; Failure; Follow-Up Studies; Health; Heme; Hippocampus; Homeostasis; Human; Kynurenine; Lead; Ligands; Link; Literature; Machine Learning; Malignant Neoplasms; Measurement; Measures; Mediating; Memantine; Metabolic; Microsomes; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Property; Public Health; Quinolinic Acid; Rapid screening; Regulation; Research; Role; Series; Site; Structure; Symptoms; Testing; Therapeutic; Triage; Tryptophan; Tryptophanase; Ubiquitin; analog; blood-brain barrier permeabilization; chemical synthesis; donepezil; enzyme activity; enzyme pathway; in vitro activity; methyl tryptophan; neurotoxic; neurotoxicity; novel; novel strategies; pharmacologic; prevent; remediation; restoration; small molecule; therapeutic target; tool; translational neuroscience; tryptophan analog; virtual

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.

神经退行性疾病是一种新兴的公共卫生危机，阿尔茨海默病 (AD) 是第六大死因，仅在美国就影响了 670 万名患者，迄今为止，尚未确定治愈药物和常用疗法（多奈哌齐、美金刚）。缓解症状，但对治疗潜在病症完全无效。当代文献表明，神经毒性犬尿氨酸途径 (KP) 代谢物的积累可能会促进 AD 的发病机制。代谢物喹啉酸 (QUIN) 会激动 N-甲基-D-天冬氨酸 (NMDA) 受体，并产生广谱神经毒性，特别是在海马体和纹状体中。值得注意的是，海马体的神经变性是 AD 痴呆的一个标志。 , QUIN 生物合成的调节为 AD 的治疗提供了一种有吸引力的方法。在拟议的研究中，我们的目标是调节 QUIN 生物合成。我们的目标不是靶向血红素依赖性 TDO 活性位点，而是通过靶向色氨酸 2,3-双加氧酶 (TDO) 来在中枢神经系统内进行。靶向在活性四聚体的稳定性中起关键作用的非催化结合位点 该研究的中心假设是小分子介导的该非催化位点的不稳定。构成了一种调节神经毒性 KP 代谢物的新方法，因此也是一种治疗 AD 的新方法，我们将通过两个互补的目标来检验这一假设，目标 1 将利用计算模型和化学合成来提供非催化位点选择性。 TDO 的小分子降解剂将通过一系列生化测定来评估目标 1 中产生的化合物的治疗活力。具体来说，将通过 ELISA 测定定量测量每种化合物的 TDO 降解效果。 KP 代谢物分析和等温量热法将通过 MDCK 和微粒体稳定性测定来评估选定化合物的药代动力学特征，这些目标将提供 CNS 渗透性 TDO 降解剂并表征其对神经毒性 KP 代谢物传播的药理学作用。鉴定出的化合物可以作为转化神经科学后续研究的有价值的工具化合物，以探究 KP 代谢物在 AD 发病机制中的作用。