Amadorins for Ameliorating Alzheimer's Disease and Related Dementias (ADRD)

Amadorins 用于改善阿尔茨海默病和相关痴呆症 (ADRD)

• 批准号: 10819236
• 负责人: RAJA G KHALIFAH
• 金额: $ 5万
• 依托单位: PRAETEGO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10819236
• 关键词: Advanced Glycosylation End Products; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Antioxidants; Binding; Brain; Catalysis; Clinical; Copper; Dementia; Disease; Disease Progression; Economic Burden; Exhibits; Free Radicals; Glucose; Health system; Impaired cognition; Ions; Iron; Metals; Nerve Degeneration; Neurons; Onset of illness; Oxidation-Reduction; Patients; Persons; Pharmaceutical Preparations; Population; Proteins; Public Health; Reactive Oxygen Species; Therapeutic; Therapeutic Agents; Transgenic Mice; Virulence Factors; adduct; ascorbate; chemical reaction; diabetic rat; drug candidate; human old age (65+); inhibitor; mild cognitive impairment; novel; novel therapeutics; oxidation; pre-clinical; prevent; tau Proteins; therapeutically effective

PROJECT SUMMARY Alzheimer’s Disease (AD) and related dementias (ADRD) are recognized as major public health issues that are projected to worsen in the aging U.S. population — the number of people of age 65 and older in the U.S. will reach 88 million by 2050. However, despite intensive efforts, there is an absence of sufficiently effective therapeutic options. Advanced glycation end products (AGE) formation is an established pathogenic factor in AD progression, impacting both amyloid beta and tau. Brains are replete with glucose and ascorbate, both of which are AGE precursors. AGE formation is initiated by the breakdown of glucose adducts on proteins via an oxidative chemical reaction requiring redox metal ion catalysis, and it is known that AD progression leads to brain accumulation of pro-oxidant copper and iron. These AGE accelerants generate toxic free radicals and reactive oxygen species (ROS) that can independently cause neuronal damage. Our hypothesis is that a drug candidate that: (1) is brain penetrant, (2) inhibits AGE formation, and (3) reduces oxidation by redox metal ions will exhibit efficacy in treating AD/ADRD. We advance in this proposal the novel “Amadorin” drug candidate PTG-630, a potent inhibitor of advanced glycation end products (AGEs) that also has the dual potential as an antioxidant due to its binding of redox metal ions, particularly Cu2+. We previously discovered that PTG-630 prevents mild cognitive impairment in diabetic rats and in a transgenic mouse model of AD when treatment was begun at onset of disease. We now propose to evaluate the therapeutic potential of PTG-630 in reversing established cognitive dysfunction and neurodegeneration in multiple animal models of AD, as this is the most likely scenario for clinical use of a therapeutic agent.

项目摘要 阿尔茨海默病（AD）和相关痴呆（ADRD）被认为是主要的公共卫生问题， 预计美国人口老龄化将恶化-美国65岁及以上的人口数量将 到2050年达到8800万。然而，尽管作出了大量努力， 治疗选择晚期糖基化终产物（AGE）的形成是AD的一个重要致病因素 进展，影响淀粉样蛋白β和tau。大脑中充满了葡萄糖和抗坏血酸， 是AGE前体。AGE的形成是由蛋白质上的葡萄糖加合物通过氧化降解引发的。 这是一种需要氧化还原金属离子催化的化学反应，并且已知AD进展导致脑损伤。 促进氧化剂铜和铁的积累。这些AGE促进剂产生有毒的自由基和活性 氧物种（ROS），可以独立地引起神经元损伤。我们的假设是一种候选药物 这三种物质：（1）是脑渗透剂，（2）抑制AGE形成，（3）通过氧化还原金属离子减少氧化， 治疗AD/ADRD的有效性。我们在这项提案中提出了新的“Amadorin”候选药物PTG-630， 一种有效的晚期糖基化终产物（AGEs）抑制剂，也具有作为抗氧化剂的双重潜力， 与其结合氧化还原金属离子，特别是Cu 2+有关。我们以前发现PTG-630可以预防轻度的 在糖尿病大鼠和AD转基因小鼠模型中，当在发病时开始治疗时， 疾病。我们现在建议评估PTG-630在逆转已建立的认知障碍方面的治疗潜力。 在多种AD动物模型中，这是最有可能的临床应用场景， 治疗剂的用途。