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: 9927153
• 负责人: CORINNE ELIZABETH AUGELLI-SZAFRAN
• 金额: $ 80.57万
• 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: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9927153
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Attention; Attenuated; Behavioral; Binding; Binding Sites; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain; Cells; Chemosensitization; Cocaine; Cognition; Cognitive; Cognitive deficits; Complex; Development; Docking; Dopamine; Dose; Drug Design; Drug Kinetics; Feedback; Functional disorder; Genetic Transcription; Goals; HIV; HIV Seropositivity; HIV-1; HIV-associated neurocognitive disorder; Homeostasis; Human; Impaired cognition; Impairment; In Vitro; Incidence; Individual; Infection; Kinetics; Lead; Learning; Ligands; Mediating; Memory; Metabolic; Modeling; Moods; Mus; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neurologic; Neuroprotective Agents; Patients; Penetration; Performance; Periodicity; Permeability; Persons; Pharmaceutical Chemistry; Pharmacology; Pharmacology Study; Pharmacotherapy; Physiological; Play; Population; Prevention; Prevention strategy; Property; Proteins; Public Health; Publishing; Quinazolines; Research; Research Personnel; Rewards; Role; Series; Severities; Site; Solubility; Structure; Structure-Activity Relationship; Synapses; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Trans-Activators; Transgenic Mice; Transgenic Organisms; Virus Diseases; Virus Replication; Work; analog; antiretroviral therapy; attenuation; base; behavioral pharmacology; behavioral study; blood-brain barrier penetration; conditioned place preference; design; dopamine transporter; dopaminergic neuron; drug of abuse; genetic regulatory protein; improved; in silico; in vivo; lead optimization; lead series; monoamine; mutant; neuroAIDS; neurotoxicity; neurotransmission; novel; novel strategies; prevent; reuptake; small molecule; transmission process; uptake

PROJECT SUMMARY 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 全球有超过 3700 万人感染人类免疫缺陷病毒 (HIV)， 仍然是一个全球性的公共卫生问题。尽管抗逆转录病毒疗法（ART）得到广泛使用，但高达 70% 的 HIV 阳性个体患有认知和行为缺陷，统称为 HIV 相关缺陷 神经认知障碍（HAND），目前尚无可用的治疗方案。的汇聚线 有证据表明，HIV-1 转录反式激活蛋白 (Tat) 在导致 HAND 中的神经毒性和认知障碍。 HIV-1 Tat 通过与关键的相互作用发挥其神经毒性 蛋白质，例如中枢神经系统 (CNS) 中的单胺转运蛋白。失调 HAND 中的多巴胺 (DA) 神经传递通过 Tat 蛋白与 DA 的直接相互作用发生 转运蛋白（DAT），对于维持 DA 稳态至关重要，也是可卡因的靶标。虽然大多数艺术 不能有效地穿过血脑屏障，Tat 诱导的 DA 水平增加会加速病毒复制 大脑。此外，滥用药物，例如可卡因，会加剧神经损伤。我们发表的作品 已证明 Tat 诱导的 DAT 抑制是通过 Tat 与变构结合位点的结合介导的 DAT，不是通过与 DA 吸收位点相互作用。这为解决这一问题的新方法提供了基础 通过开发化合物通过变构机制减弱 Tat 与 DAT 的结合来解决这个问题。我们最近的 对 DAT 小分子变构配体的研究表明，这些化合物能够减弱 Tat 介导的对 DAT 的影响，从而为开发治疗干预措施提供了潜在的机会 手的治疗。本文提出的研究工作是探索 Tat-DAT 的破坏的假设 与 DAT 小分子变构配体的相互作用，对正常 DA 摄取的干扰最小，将具有 预防 HAND 神经认知功能障碍的治疗潜力。我们研究的首要目标是 优化先导化合物并在动物模型中进行概念验证药理学研究。对此 最后，拟议工作的具体目标是：（1）设计和合成新型变构 使用计算机特性预测具有改进的物理化学和药代动力学特性的配体 与 DAT-Tat 复杂模型的计算对接研究，(2) 表征了 在体外与人 DAT 进行化合物分析，以确定理化性质得到改善的优化化合物 可用于缓解 Tat 诱导的 DAT 功能障碍，以及 (3) 确定所选药物的功效 减轻 Tat 介导的认知缺陷和可卡因对诱导性 Tat 的奖励作用的化合物 转基因小鼠体内。这项合作努力涉及具有医学互补专业知识的研究人员 化学、药物设计以及生化和行为研究，其长期目标是开发药物 HIV 阳性患者的 HAND 治疗。