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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要超过3700万人患有人类免疫缺陷病毒（HIV）感染在全球范围内，这仍然是全球公共卫生问题。尽管广泛使用抗逆转录病毒疗法（ART），多达70％的HIV阳性个体患有认知和行为缺陷统称为艾滋病毒相关的神经认知障碍（手），用于目前尚无治疗选择。融合的证据线表明 HIV-1转录剂（TAT）蛋白在引起神经毒性方面起着至关重要的作用手头的认知障碍。 HIV-1 TAT通过与关键的蛋白质，例如中枢神经系统（CNS）中的单胺转运蛋白。这多巴胺（DA）神经传递的失调是通过直接相互作用发生的 TAT蛋白与DA转运蛋白（DAT），这对于维持DA稳态至关重要和可卡因的目标。虽然大多数艺术无法有效地越过血脑屏障，但诱导的DA水平升高会加速大脑的病毒复制。而且，药物滥用，例如可卡因，加剧神经系统障碍。我们发表的工作有证明TAT诱导的DAT抑制是通过TAT与变构结合的结合来介导的在DAT上绑定站点，而不是与DA摄取站点进行交互。这为A提供了基础通过开发化合物减弱TAT结合的新方法来解决该问题通过变构机制。我们最近对小分子变构配体的研究 DAT揭示这些化合物能够减弱TAT介导的对DAT的影响，从而提供了一个潜在的机会来开发治疗治疗的治疗干预措施。本文提出的研究工作是探讨tat-dat中断的假设与DAT的小分子变构配体的相互作用，正常DA的破坏最小吸收，将具有预防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铅化合物并执行概念验证动物模型的药理研究。为此，具体的目标是提出的努力是：（1）设计和合成新型的变构配体，并改进在硅特性预测中使用的物理化学和药代动力学特性使用DAT-TAT复合模型的计算对接研究，（2）表征变构化合物在体外与人DAT的相互作用，以鉴定优化化合物与改进的理化特性可用于减轻TAT诱导的功能障碍 dat，（3）确定所选化合物在衰减Tat介导的疗效可卡因在体内诱导型TAT转基因小鼠中可卡因的认知缺陷和奖励作用。这协作努力涉及具有补充药物化学专业知识的研究人员，药物设计以及生化和行为研究的长期目标在HIV阳性患者中治疗手的药物。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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.)
影响因子：
0
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