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

• 批准号: 8736399
• 负责人: HARRIS A GELBARD
• 金额: $ 67.39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/8736399
• 关键词: AIDS neuropathy; Affect; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Architecture; Atazanavir; Brain; Brain Diseases; CD34 gene; Cells; Chemosensitization; Cognitive; Combination Drug Therapy; Combined Modality Therapy; Complement; Complex; DNA; Data; Development; Disease; Drug Combinations; Drug Formulations; Drug toxicity; Endosomes; Ensure; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Exposure to; Family member; Genetic; Genomics; Goals; HIV-1; Half-Life; Hematopoietic stem cells; Histone Deacetylase Inhibitor; Homeostasis; Human; Immune; Immunoblotting; In Vitro; Infection; Inflammation; Injury; Lead; Leukocytes; Life; Life Cycle Stages; Measures; Mediating; Microfluidics; Microglia; Microscopic; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mononuclear; Mus; National Institute of Mental Health; Nature; Neurocognitive; Neurons; Neurotoxins; Pathway interactions; Patients; Peripheral; Phagocytes; Pharmaceutical Preparations; Phosphotransferases; Protease Inhibitor; Protein Family; Proteins; Proteomics; RNA Interference; Recombinants; Residual state; Ritonavir; Role; Signal Transduction; Signaling Protein; Site; Synapses; Tenofovir; Testing; Therapeutic Effect; Vesicle; Viral; Viral Antigens; Viral Load result; Virus; Virus Diseases; Work; antiretroviral therapy; base; brain tissue; drug efficacy; emtricitabine; immune function; in vitro Model; in vivo; in vivo Model; intravital microscopy; kinase inhibitor; macrophage; member; monocyte; mouse model; nanoformulation; neuroinflammation; neuroprotection; neurotoxic; neurotoxicity; novel; particle; prostratin; public health relevance; relating to nervous system; research study; response; restoration; trafficking; viral RNA

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(申请人提供)：本申请是基于一项偶然发现，即URMC-099可以显著增强长效抗逆转录病毒疗法的抗病毒活性。URMC-099被开发为一种新的领先的一类混合谱系激酶(MLK)抑制剂，正在开发中，用于治疗HIV-1相关的神经认知障碍(HAND)，意外地被发现增强纳米制剂利托那韦增强的阿扎那韦(NanATV/r)的抗逆转录病毒作用。这种药物组合显著减少了残留的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，增强纳米ATV/r与病毒生命周期中的病毒颗粒之间的相互作用，从而促进了NanATV/r的治疗效果。在这里，我们将确定URMC-099对MLK的抑制是否参与了ATV/r在内体中的作用，或者这一发现是否由于对该药物靶向的其他激酶的影响。我们最近的研究表明，URMC-099减少了体内的神经炎症，对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感染患者的ATV蓄积和半衰期，这预示着这种联合化疗是安全的。 在保护神经动态平衡的同时，在中枢神经系统实现病毒根除。我们提出了三个具体的目标来进一步描述这些相互作用：(1)我们将阐明URMC-099促进单核巨噬细胞(MP；单核细胞来源的巨噬细胞[MDM]和小胶质细胞)中与MLKs和其他URMC-099靶向的其他相关激酶(包括介导炎症的激酶)有关的纳米抗逆转录病毒反应的途径(机制)，并确定病毒是否可以被根除或仅仅被抑制。(2)评估目标1中确定的RAB家族成员对我们手部模型中URMC-099和NanoArt潜在药物毒性的影响。为此，我们将研究它在URMC-099和NanoArt治疗后对暴露于HIV-1神经毒素的MP和突触网络的调节作用。我们将使用体内模型来进一步了解RABS在MLK激活和突触树突损伤中的作用，以保护大脑免受进一步损伤。最后，在(3)中，我们将在我们的人源化CD34移植神经艾滋病模型中验证纳米配方抗逆转录病毒疗法(NanoArt)和URMC-099在清除中枢神经系统持续感染的病毒库方面的有效性。总之，这些目标将推动我们根除长期持续感染中枢神经系统MP的方法，同时保留疾病中的突触结构和功能。