PTPRD phosphatase inhibitors for stimulant use disorders

PTPRD 磷酸酶抑制剂治疗兴奋剂使用障碍

基本信息

批准号：
10710969
负责人：
George Richard Uhl
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10710969
关键词：
3xTg-AD mouse Aging Alzheimer&apos s Disease Apolipoprotein E Behavioral Biodistribution Brain Dementia Development Dietary intake Flavones Flavonols Functional disorder Genes Genetic Glycogen Synthase Kinases Histologic In Vitro Lead Modeling Modification Mus Natural Products Neurofibrillary Tangles Pathogenicity Pathologic Pathology Pharmaceutical Preparations Phosphopeptides Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Positioning Attribute Property Protein Dephosphorylation Protein Tyrosine Kinase Protein Tyrosine Phosphatase Role Specificity Structure Structure-Activity Relationship Testing Toxic effect Translations Tyrosine Variant Work analog drug candidate drug market glycogen synthase kinase 3 beta hyperphosphorylated tau improved in silico in vivo neuropathology novel novel strategies novel therapeutics off-target site phosphatase inhibitor positive allosteric modulator prevent receptor stimulant use disorder tau Proteins therapy development

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) receives pathogenic contributions from genetics [1, 2] and from environmental influences that include dietary intake of flavonols > flavones [4-8]. Neurofibrillary tangles (NFTs) rich in hyper- phosphorylated tau protein [10] are prominent features of AD neuropathology. NFT densities correlate well with the degree of AD dementia [15] [18] and are influenced by variation in the ApoE and PTPRD genes [3]. One approach to altering tau/NFT pathophysiology is to reduce activities of the kinases that hyper- phosphorylate tau. The glycogen synthase kinases GSK3α and GSK3β are prominent tau phosphorylators [19]. GSK3α and GSK3β are activated by phosphorylation of their own tyrosines (pY279 and pY216) by known tyrosine kinases [20] [21, 22]. Increasing activity of tyrosine phosphatase(s) that dephosphorylate and reduce activities of brain GSK3α and GSK3β thus provides a novel approach to reducing tau pathology in AD. Evidence (much developed during our prior NIA supplement support) now supports roles for: a) the receptor type protein tyrosine phosphatase PTPRD as both a key physiological phosphatase for phospho (pY) GSK3α and GSK3β and a novel target for decreasing pathological AD tau hyperphosphorylation, b) flavonols as lead compound PTPRD positive allosteric modulators (PAMs) that increase this desired PTPRD activity and c) structure activity relationships for natural product and novel flavonol analogs that supports the likelihood that further modifications will provide novel drug candidates. We will enhance this evidence and move toward translation by testing hypotheses that a) 8- position-substituted and other flavonol analogs will display enhanced positive allosteric modulation of PTPRD dephosphorylation of GSK3β/GSK3α b) this enhancement will display specificity with respect to activities at related phosphatases c) optimal analogs will display improved drug-like properties in silico and in vivo. Each of these attributes will allow us to develop and select improved, specific PTPRD PAMs that can reduce progression to AD deficits during aging. We will test these hypothesis and support development and translation of PTPRD PAMs in several ways: 1) We will synthesize and test novel flavonol analogs as improved PTPRD PAMs, testing these structures in vitro, refining our in silico models and nominating/synthesizing/testing new structures on the basis of these results, testing specificities vs other PTPRD substrate phosphopeptides and off-target sites of action of currently marketed drugs. We will test the most promising PTPRD PAMs in vivo for gross, histological or behavioral toxicities, biodistribution (including brain) and evidence for target engagement. We will begin testing of the best candidates in aging 3xTg-AD mice with or without reduced PTPRD expression. This work will advance our understanding of AD pathophysiology, validate novel approaches to PTPRD positive allosteric modulation and provide a basis for development of interventions that can prevent and/or treat key aspects of AD.

项目概要/摘要阿尔茨海默病 (AD) 的致病因素来自遗传学 [1, 2] 和环境的影响包括饮食中黄酮醇的摄入量>黄酮类[4-8]。磷酸化 tau 蛋白 [10] 是 AD 神经病理学的突出特征，与 NFT 密度密切相关。 AD 痴呆的程度 [15] [18]，并受到 ApoE 和 PTPRD 基因变异的影响 [3]。改变 tau/NFT 病理生理学的一种方法是减少过度激活的激酶的活性。磷酸化 tau 糖原合酶激酶 GSK3α 和 GSK3β 是重要的 tau 磷酸化因子。 [19] GSK3α 和 GSK3β 通过自身酪氨酸（pY279 和 pY216）的磷酸化被激活。酪氨酸激酶 [20] [21, 22] 增加去磷酸化和减少酪氨酸磷酸酶的活性。因此，大脑 GSK3α 和 GSK3β 的活动为减少 AD 中的 tau 病理学提供了一种新方法。证据（在我们之前的 NIA 补充支持期间得到了很多发展）现在支持以下作用：a) 受体类型蛋白酪氨酸磷酸酶 PTPRD 作为磷酸 (pY) GSK3α 的关键生理磷酸酶和 GSK3β 以及减少病理性 AD tau 过度磷酸化的新靶标，b) 黄酮醇作为铅复合 PTPRD 正变构调节剂 (PAM)，可增加所需的 PTPRD 活性，并且 c) 天然产物和新型黄酮醇类似物的结构活性关系支持以下可能性：进一步的修改将提供新的候选药物。通过测试 a) 8 位取代和其他黄酮醇类似物将显示的假设进行翻译增强 GSK3β/GSK3α 的 PTPRD 去磷酸化的正变构调节 b) 这种增强将显示相关磷酸酶活性的特异性 c) 最佳类似物将显示改进这些属性中的每一个都将使我们能够开发和选择改进的、特定的 PTPRD PAM 可以减少衰老过程中 AD 缺陷的进展。我们将通过多种方式测试这些假设并支持 PTPRD PAM 的开发和翻译：1) 我们将合成并测试新型黄酮醇类似物作为改进的 PTPRD PAM，在体外测试这些结构，完善我们的计算机模型并根据这些结果提名/合成/测试新结构，测试与其他 PTPRD 底物磷酸肽相比的特异性以及当前的脱靶作用位点我们将对最有前途的 PTPRD PAM 进行体内总体、组织学或行为学测试。我们将开始测试最佳的毒性、生物分布（包括大脑）和目标参与的证据。在有或没有减少 PTPRD 表达的衰老 3xTg-AD 小鼠中进行候选研究这项工作将推进我们的研究。了解 AD 病理生理学，验证 PTPRD 正变构调节的新方法，以及为制定预防和/或治疗 AD 关键方面的干预措施提供基础。