Novel Kinase and Nanoformulated Protease Inhibitors for Eradication of CNS HIV-1

用于根除 CNS HIV-1 的新型激酶和纳米制剂蛋白酶抑制剂

基本信息

批准号：
9302543
负责人：
HARRIS A GELBARD
金额：
$ 63.09万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-16 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302543
关键词：
AGFG1 gene Affect Anti-Retroviral Agents Antibodies Antigens Antiviral Agents Architecture Atazanavir Brain Brain Diseases CD34 gene CEP 1347 Cells Central Nervous System Infections Chemosensitization Cognitive Combination Drug Therapy Combined Modality Therapy Complement Complex DNA Data Development Disease Drug Combinations Drug toxicity Endosomes Ensure Enzyme Inhibitor Drugs Exposure to Family member Formulation Genetic Genomics Goals HIV-1 HIV-associated neurocognitive disorder Half-Life Hematopoietic stem cells Histone Deacetylase Inhibitor Homeostasis Human Immune In Vitro Infection Inflammation Injury Lead Leukocytes Life Cycle Stages Measures Mediating Microfluidics Microglia Microscopic Modeling Molecular Monomeric GTP-Binding Proteins Mononuclear Mus National Institute of Mental Health Nature Neurons Neurotoxins Pathway interactions Patients Peripheral Phagocytes Pharmaceutical Preparations Pharmacological Treatment Phosphotransferases Protease Inhibitor Protein Family Proteins Proteomics RNA Interference Recombinants Residual state Ritonavir Role Signal Pathway Signal Transduction Signaling Protein Site Synapses Tenofovir Testing Therapeutic Effect Vesicle Viral Viral Load result Viral reservoir Virus Virus Diseases Work antiretroviral therapy base brain tissue drug efficacy emtricitabine experimental study immune function in vitro Model in vivo in vivo Model intravital microscopy kinase inhibitor macrophage member monocyte mouse model nanoformulation neuroAIDS neuroinflammation neuroprotection neurotoxic neurotoxicity novel particle prostratin public health relevance relating to nervous system response restoration targeted agent trafficking viral RNA

项目摘要

DESCRIPTION (provided by applicant): This application is based on the serendipitous finding that URMC-099 can significantly boost antiviral activities of long acting antiretroviral therapy. Developed as a novel lead first-in-class mixed lineage kinase (MLK) inhibitor under development for use against HIV-1 associated neurocognitive disorders (HAND), URMC-099 was unexpectedly found to potentiate antiretroviral actions of nanoformulated ritonavir- boosted atazanavir (nanoATV/r). This drug combination led to a marked reduction of residual HIV-1 infection. URMC-099 facilitated nanoATV/r therapeutic effects by affecting the expression of the Rab family proteins that regulate endosomal vesicle trafficking, augmenting interactions between nanoATV/r and viral particles during the viral life cycle. Herein we will determine whether MLK inhibition from URMC-099 is involved in ATV/r's actions in the endosome, or if the findings are due to effects on other kinases targeted by this agent. Our recent demonstration that URMC-099 reduces neuroinflammation and is neuroprotective against HIV-1 proteins in vivo, and that the non-selective MLK inhibitor, CEP-1347 can increase ATV accumulation and half-life in HIV-1 infected patients bodes very well for this combination of chemotherapy to safely achieve viral eradication in the CNS while protecting neural homeostasis. We propose three specific aims to further delineate these interactions: (1) We will elucidate the pathways (mechanisms) responsible for URMC-099 facilitated nanoformulated antiretroviral responses in mononuclear phagocytes (MP; monocyte-derived macrophages [MDM] and microglia) in relation to MLKs and other related kinases targeted by URMC-099 (including kinases that mediate inflammation) and determine whether virus can be eradicated or merely suppressed. (2) To assess the impact of Rab family members identified in Aim 1 on potential drug toxicities from URMC-099 and nanoART in our models of HAND. To this end, we will investigate its roles in regulating MP and synaptic networks exposed to HIV-1 neurotoxins after URMC-099 and nanoART treatment. We will use in vivo models to further understand the role of Rabs as they relate to MLK activation and synaptodendritic damage with the idea of protecting the brain against further injuries. Finally, in (3) we will validate the utility of nanoformulated antiretrovral therapy (nanoART) and URMC-099 in clearance of persistently infected viral reservoirs in the CNS in our humanized CD34 engrafted model of neuroAIDS. Together, these aims will advance our approach to eradication of long-lived persistent infection of CNS MP while preserving synaptic architecture and function in disease.

描述（由申请人提供）：本申请基于URMC-099可以显着增强长效抗逆转录病毒疗法的抗病毒活性的偶然发现。 URMC-099 是一种新型领先的一流混合谱系激酶 (MLK) 抑制剂，正在开发中用于治疗 HIV-1 相关神经认知障碍 (HAND)，出人意料地发现，URMC-099 可以增强纳米制剂利托那韦增强阿扎那韦 (nanoATV) 的抗逆转录病毒作用。 /r）。这种药物组合显着减少了残留的 HIV-1 感染。 URMC-099 通过影响调节内体囊泡运输的 Rab 家族蛋白的表达、增强病毒生命周期中 nanoATV/r 与病毒颗粒之间的相互作用来促进 nanoATV/r 的治疗效果。在此，我们将确定 URMC-099 的 MLK 抑制是否与 ATV/r 在内体中的作用有关，或者这些发现是否是由于对该药物靶向的其他激酶的影响所致。我们最近证明 URMC-099 可以减少神经炎症，并对体内 HIV-1 蛋白具有神经保护作用，并且非选择性 MLK 抑制剂 CEP-1347 可以增加 HIV-1 感染患者中 ATV 的积累和半衰期，这预示着这种化疗组合可以安全地实现中枢神经系统病毒根除，同时保护神经稳态。我们提出三个具体目标来进一步描述这些相互作用：（1）我们将阐明 URMC-099 促进单核吞噬细胞（MP；单核细胞衍生巨噬细胞 [MDM] 和小胶质细胞）中纳米制剂抗逆转录病毒反应的途径（机制） URMC-099 靶向的 MLK 和其他相关激酶（包括介导炎症的激酶）并确定是否可以根除病毒或者只是被压制。 (2) 评估目标 1 中确定的 Rab 家族成员对我们的 HAND 模型中 URMC-099 和 nanoART 的潜在药物毒性的影响。为此，我们将研究 URMC-099 和 nanoART 治疗后其在调节暴露于 HIV-1 神经毒素的 MP 和突触网络中的作用。我们将使用体内模型来进一步了解 Rabs 的作用，因为它们与 MLK 激活和突触树突损伤有关，以保护大脑免受进一步损伤。最后，在（3）中，我们将验证纳米制剂抗逆转录疗法（nanoART）和URMC-099在我们的人源化CD34植入神经艾滋病模型中清除中枢神经系统中持续感染的病毒库的效用。总之，这些目标将推进我们根除 CNS MP 长期持续感染的方法，同时保留疾病中的突触结构和功能。