Identification of CNS-Penetrant Tryptophan 2,3-Dioxygenase Degrading Ligands

CNS 渗透色氨酸 2,3-双加氧酶降解配体的鉴定

• 批准号: 10511398
• 负责人: Ryan A Altman
• 金额: $ 23.59万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511398
• 关键词: Active Learning; Active Sites; Affinity; Alzheimer' s Disease; Amino Acids; Basic Science; Binding; Binding Sites; Biochemical; Biological Assay; Biology; Brain; Catabolism; Cell model; Cell physiology; Central Nervous System Diseases; Chemistry; Clinical Research; Clinical Trials; Drug Industry; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; FDA approved; Future; Heme; Human; Huntington Disease; Immunology; In Vitro; Institution; Joints; Knowledge; Kynurenine; Lead; Ligands; Link; Machine Learning; Malignant Neoplasms; Measures; Mental Depression; Metabolism; Nerve Degeneration; Neurons; New Agents; Parkinson Disease; Pathway interactions; Peripheral; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Pilot Projects; Property; Prosthesis; Proteins; Resistance; Series; Signal Transduction; Site; Solid; Solubility; Tryptophan; Tryptophanase; Ubiquitin; Ubiquitination; Up-Regulation; Ursidae Family; Work; anxiety-related behavior; design; drug development; drug distribution; in vitro Assay; in vivo; inhibitor; innovation; neurogenesis; neuropsychiatric disorder; novel; preclinical trial; protein degradation; scaffold; small molecule; therapeutic development; tool; virtual

ABSTRACT Tryptophan 2,3-dioxygenase (TDO) is a key modulator of physiological neurogenesis and anxiety-related behavior. Misregulated neuronal TDO activity causes elevated levels of tryptophan-kynurenine pathway metabolites, which in turn, causes depression, brain degeneration, and neurodegenerative Alzheimer's, Parkinson's, and Huntington's diseases. However, a critical need remains for identifying new agents that function through innovative mechanisms to probe a range of pharmacological hypotheses regarding central TDO action, ultimately advancing our overall pharmacological knowledge, and to also serve as leads for downstream medicinal chemistry optimization, thus helping people live long healthy lives. To identify innovative inhibitors, we engaged in a joint basic science-clinical study that identified a non-catalytic L-tryptophan (L-Trp) binding site in human TDO that binds L-Trp surprisingly much tighter than the catalytic heme site. The newly discovered L-Trp binding site is involved in regulating TDO activity and stability by suppressing ubiquitin-dependent degradation when loaded with L-Trp. This finding has inspired us to propose a central hypothesis that this newly discovered signaling site is an Achilles' heel of TDO for drug development. This application will fill the critical need to identify CNS-penetrant protein-degrading ligands for exploring their biomedical potential. Towards this end, we will employ our rigorous understanding of the underlying chemistry and biology to design compounds with a novel mode of action that destabilize the signaling site of TDO or bind without enhancing the protein stability. These agents will not target the catalytic activity of TDO but instead will disrupt its degradation resistance signal. We will assess the effects of promising compounds on human TDO in cellular models to validate the innovative approach and target. In the end, this work will open the door for designing revolutionarily new centrally-active inhibitors targeting human TDO.

抽象的 色氨酸 2,3-双加氧酶 (TDO) 是生理神经发生和焦虑相关的关键调节剂 行为。神经元 TDO 活性失调导致色氨酸-犬尿氨酸通路水平升高 代谢物，进而导致抑郁症、大脑退化和神经退行性阿尔茨海默病， 帕金森病和亨廷顿舞蹈病。然而，仍然迫切需要确定能够发挥作用的新药物 通过创新机制探索一系列有关中枢 TDO 作用的药理学假设， 最终提高我们的整体药理学知识，并为下游提供线索 药物化学优化，从而帮助人们健康长寿。为了识别创新抑制剂，我们 参与了一项基础科学与临床联合研究，确定了非催化 L-色氨酸 (L-Trp) 结合位点 令人惊讶的是，人类 TDO 与 L-Trp 的结合比催化血红素位点紧密得多。新发现的L-色氨酸 结合位点通过抑制泛素依赖性降解来调节 TDO 活性和稳定性 当加载 L-Trp 时。这一发现启发我们提出一个中心假设，即这一新发现 信号位点是药物开发中 TDO 的致命弱点。该应用程序将满足识别的关键需求 中枢神经系统渗透蛋白降解配体，用于探索其生物医学潜力。为此，我们将 利用我们对基础化学和生物学的严格理解来设计具有新颖性的化合物 破坏 TDO 信号位点稳定或结合而不增强蛋白质稳定性的作用模式。这些 试剂不会针对 TDO 的催化活性，而是会破坏其抗降解信号。我们 将在细胞模型中评估有前途的化合物对人类 TDO 的影响，以验证创新 方法和目标。最终，这项工作将为设计革命性的新型中央主动式装置打开大门。 针对人类 TDO 的抑制剂。