Allosteric Modulators of Dopamine Transporter as Therapeutic Agents for NeuroAIDS

多巴胺转运蛋白的变构调节剂作为神经艾滋病的治疗剂

• 批准号: 10756629
• 负责人: CORINNE ELIZABETH AUGELLI-SZAFRAN
• 金额: $ 14.83万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10756629
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Address; Animal Model; Attenuated; Behavioral; Binding; Binding Sites; Biochemical; Brain; Central Nervous System; Cocaine; Cognitive; Cognitive deficits; Complex; Development; Docking; Dopamine; Drug Design; Drug Kinetics; Functional disorder; Genetic Transcription; Goals; HIV; HIV Seropositivity; HIV-1; HIV-associated neurocognitive disorder; Homeostasis; Human; Impaired cognition; Impairment; In Vitro; Individual; Infection; Ligands; Mediating; Modeling; Neurocognitive; Neurocognitive Deficit; Neurologic; Patients; Persons; Pharmaceutical Chemistry; Pharmacology Study; Pharmacotherapy; Play; Population; Prevention; Property; Proteins; Public Health; Publishing; Research; Research Personnel; Rewards; Role; Site; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Trans-Activators; Transcription Coactivator; Transgenic Mice; Virus Diseases; Virus Replication; Work; antiretroviral therapy; behavioral study; blood-brain barrier crossing; design; dopamine transporter; drug of abuse; efficacy evaluation; improved; in silico; in vivo; lead optimization; monoamine; neuroAIDS; neurotoxicity; neurotransmission; novel; novel strategies; small molecule; uptake

Project Summary/Abstract More than 37 million people are living with Human Immunodeficiency Virus (HIV) infection worldwide which continues to be a global public health problem. Despite the widespread use of antiretroviral therapy (ART), up to 70% of HIV-positive individuals suffer from cognitive and behavioral deficits collectively known as HIV-associated neurocognitive disorders (HAND), for which no therapeutic options are currently available. Converging lines of evidence indicate that the HIV-1 transactivator of transcription (Tat) protein plays a crucial role in causing neurotoxicity and cognitive impairment in HAND. HIV-1 Tat exerts its neurotoxicity through interaction with crucial proteins, such as the monoamine transporters in the central nervous system (CNS). The dysregulation of dopamine (DA) neurotransmission in HAND occurs through direct interaction of Tat protein with the DA transporter (DAT) which is essential for maintaining DA homeostasis and a target of cocaine. While most ARTs cannot efficiently cross the blood-brain barrier, Tat- induced increase in DA levels accelerates viral replication in the brain. Moreover, drugs of abuse, such as cocaine, exacerbate neurological impairments. Our published work has demonstrated that Tat-induced inhibition of DAT is mediated by binding of Tat to allosteric binding site(s) on DAT, not by interacting with the DA uptake site. This provides a basis for a novel approach to address the problem by developing compounds to attenuate Tat binding to DAT by an allosteric mechanism. Our recent studies with small molecule allosteric ligands of DAT reveal that these compounds are capable of attenuating Tat-mediated effects on DAT, thus providing a potential opportunity to develop therapeutic interventions for the treatment of HAND. The research effort proposed herein is to explore the hypothesis that disruption of Tat-DAT interactions with small molecule allosteric ligands of DAT, with minimal disruption of normal DA uptake, will have therapeutic potential for prevention of neurocognitive dysfunction in HAND. The primary goal of our research is to optimize lead compounds and perform proof-of-concept pharmacological studies in animal models. To this end, the specific aims to be pursed in the proposed effort are to: (1) design and synthesize novel allosteric ligands with improved physicochemical and pharmacokinetic properties using in silico property predictions and computational docking studies with DAT-Tat complex models, (2) characterize the allosteric interaction of the compounds with human DAT in vitro to identify optimized compounds with improved physicochemical properties that can be used to alleviate Tat-induced dysfunction of DAT, and (3) determine the efficacy of selected compounds in attenuating Tat-mediated cognitive deficits and rewarding effects of cocaine in inducible Tat transgenic mice in vivo. This collaborative effort involves investigators with complementary expertise in medicinal chemistry, drug design, and biochemical and behavioral studies with the long-term goal of developing drugs for the treatment of HAND in HIV-positive patients.

项目概要/摘要 超过 3700 万人感染人类免疫缺陷病毒 (HIV) 世界范围内，这仍然是一个全球公共卫生问题。尽管广泛使用 抗逆转录病毒治疗（ART），高达 70% 的 HIV 阳性个体患有认知和 行为缺陷统称为 HIV 相关神经认知障碍 (HAND)， 目前没有可用的治疗选择。汇聚的证据表明 HIV-1 转录反式激活蛋白 (Tat) 在引起神经毒性中起着至关重要的作用 和 HAND 中的认知障碍。 HIV-1 Tat 通过与 关键蛋白质，例如中枢神经系统 (CNS) 中的单胺转运蛋白。这 HAND 中多巴胺 (DA) 神经传递的失调是通过以下因素的直接相互作用发生的： 含有 DA 转运蛋白 (DAT) 的 Tat 蛋白对于维持 DA 稳态至关重要 和可卡因的目标。虽然大多数 ART 不能有效地穿过血脑屏障，但 Tat- 诱导的 DA 水平增加会加速病毒在大脑中的复制。此外，药物 滥用，如可卡因，会加剧神经损伤。我们发表的作品有 证明 Tat 诱导的 DAT 抑制是通过 Tat 与变构结合介导的 DAT 上的结合位点，而不是通过与 DA 摄取位点相互作用。这提供了一个基础 通过开发化合物来减弱 Tat 结合来解决该问题的新方法 DAT 通过变构机制。我们最近对小分子变构配体的研究 DAT 表明这些化合物能够减弱 Tat 介导的对 DAT 的影响，因此 为开发治疗 HAND 的治疗干预措施提供了潜在的机会。 本文提出的研究工作是探索 Tat-DAT 的破坏的假设 与 DAT 小分子变构配体相互作用，对正常 DA 的破坏最小 摄取，将具有预防 HAND 神经认知功能障碍的治疗潜力。 我们研究的主要目标是优化先导化合物并进行概念验证 动物模型的药理学研究。为此，要实现的具体目标 建议的努力是：（1）设计和合成具有改进的新型变构配体 使用计算机特性预测的物理化学和药代动力学特性 与 DAT-Tat 复杂模型的计算对接研究，(2) 表征变构 化合物与人 DAT 的体外相互作用，以确定优化的化合物 改善理化性质，可用于缓解 Tat 诱导的功能障碍 DAT，以及（3）确定所选化合物在减弱 Tat 介导的作用中的功效 可卡因对体内可诱导 Tat 转基因小鼠的认知缺陷和奖励作用。这 合作努力涉及在药物化学方面具有互补专业知识的研究人员， 药物设计以及生化和行为研究，其长期目标是开发 用于治疗 HIV 阳性患者的 HAND 的药物。

项目成果

Mutations of Human DopamineTransporter at Tyrosine88, Aspartic Acid206, and Histidine547 Influence Basal and HIV-1 Tat-inhibited Dopamine Transport.

• DOI: 10.1007/s11481-021-09984-5
• 发表时间: 2021-12
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Quizon PM;Yuan Y;Zhu Y;Zhou Y;Strauss MJ;Sun WL;Zhan CG;Zhu J
• 通讯作者: Zhu J

Substance abuse and neurotransmission.

• DOI: 10.1016/bs.apha.2021.10.007
• 发表时间: 2022
• 期刊: Advances in pharmacology (San Diego, Calif.)
• 作者: Davis, Sarah;Zhu, Jun
• 通讯作者: Zhu, Jun

The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases.

• DOI: 10.3390/ijms242015340
• 发表时间: 2023-10-19
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Davis SE;Cirincione AB;Jimenez-Torres AC;Zhu J
• 通讯作者: Zhu J

Mutations at tyrosine 88, lysine 92 and tyrosine 470 of human dopamine transporter result in an attenuation of HIV-1 Tat-induced inhibition of dopamine transport.

• DOI: 10.1007/s11481-015-9583-3
• 发表时间: 2015-03
• 期刊: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
• 影响因子: 6.2
• 作者: Midde, Narasimha M.;Yuan, Yaxia;Quizon, Pamela M.;Sun, Wei-Lun;Huang, Xiaoqin;Zhan, Chang-Guo;Zhu, Jun
• 通讯作者: Zhu, Jun

Mutations of tyrosine 467 in the human norepinephrine transporter attenuate HIV-1 Tat-induced inhibition of dopamine transport while retaining physiological function.

• DOI: 10.1371/journal.pone.0275182
• 发表时间: 2022
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Strauss, Matthew J.;Porter, Katherine D.;Quizon, Pamela M.;Davis, Sarah E.;Lin, Steven;Yuan, Yaxia;Martinez-Muniz, Gustavo A.;Sun, Wei-Lun;Zhan, Chang-Guo;Zhu, Jun
• 通讯作者: Zhu, Jun