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: 9107504
• 负责人: HARRIS A GELBARD
• 金额: $ 63.64万
• 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/9107504
• 关键词: Affect; Anti-Retroviral Agents; Antibodies; 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; Enzyme Inhibitors; Exposure to; Family member; Formulation; Genetic; Genomics; Goals; HIV-1; Half-Life; Health; 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; 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; Viral reservoir; 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; neuroAIDS; neurocognitive disorder; neuroinflammation; neuroprotection; neurotoxic; neurotoxicity; novel; particle; prostratin; relating to nervous system; research study; response; restoration; targeted agent; 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（由申请人提供）：该申请是基于偶然发现URMC-099可以显著提高长效抗逆转录病毒治疗的抗病毒活性。URMC-099是一种新型的领先的混合谱系激酶（MLK）抑制剂，正在开发用于治疗HIV-1相关神经认知障碍（HAND），出乎意料地发现，URMC-099可以增强纳米配方利托那韦增强的阿扎那韦（nanoATV/r）的抗逆转录病毒作用。这种药物组合导致残留HIV-1感染的显著减少。URMC-099通过影响调节内体囊泡运输的Rab家族蛋白的表达，在病毒生命周期中增加nanoATV/r与病毒颗粒之间的相互作用，促进了nanoATV/r的治疗效果。在这里，我们将确定URMC-099对MLK的抑制是否与ATV/r在内体中的作用有关，或者这些发现是由于该药物对其他靶向激酶的影响。我们最近的研究表明，URMC-099可以减少神经炎症，并在体内对HIV-1蛋白具有神经保护作用，而非选择性MLK抑制剂CEP-1347可以增加HIV-1感染患者的ATV积累和半衰期，这很好地预示着这种联合化疗的安全性