Neuroprotective and Antiviral Effects of BMD-101 and BMD-104 in HIV Infection

BMD-101 和 BMD-104 在 HIV 感染中的神经保护和抗病毒作用

• 批准号: 8131579
• 负责人: Christopher G. Conrad
• 金额: $ 24.69万
• 依托单位: BIOMEDISYN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-19 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131579
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; ART protein; Acetylcholinesterase Inhibitors; Acquired Immunodeficiency Syndrome; Address; Adolescent; Adult; Affect; Animal Model; Anti-Retroviral Agents; Antiviral Agents; Biological Assay; Brain; Cell physiology; Cells; Clinical Trials; Cognition; Data; Development; Disease; Distal; Dose; Drug Kinetics; Evaluation; HIV; HIV Envelope Protein gp120; HIV Infections; HIV neuropathy; HIV-1; Highly Active Antiretroviral Therapy; Human; Impaired cognition; In Vitro; Lead; Life Expectancy; Lymphocyte; Mediating; Mediator of activation protein; Mitochondria; Modeling; Nerve Degeneration; Nervous system structure; Neurocognitive; Neuroglia; Neurologic; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuroprotective Agents; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Property; Proteins; Rattus; Research; Safety; Sensory Disorders; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxin; Transgenic Mice; Viral; Viral Load result; base; disability; drug development; effective therapy; enantiomer; excitotoxicity; functional disability; huperzine A; in vitro Assay; in vivo; macrophage; monocyte; mouse model; neuroprotection; neurotoxic; neurotoxicity; novel; patient population; pre-clinical; prevent; public health relevance; research and development; research clinical testing; research study

DESCRIPTION (provided by applicant): The introduction and implementation of highly active antiretroviral therapy (HAART) in AIDS patients diminished HIV viral load and led to an increase in life expectancy, but HIV infection can still lead to severe complications in the nervous system such as HIV-associated neurocognitive disorders (HAND) and sensory distal neuropathy (HIV-SN). For this patient population there is currently no adjunctive and neuroprotective treatment available, but is highly needed. In HAND, the neuronal dysfunction is mainly mediated by mechanisms involving oxidative stress and excitotoxicity elicited by HIV proteins and soluble mediators released from HIV infected cells. Based on these premises, we developed a novel neurotoxicity assay for neuroprotective agents which utilizes rat and human primary neuronal cultures. With this neurotoxicity assay, we evaluated BMD-101 and BMD-104 for neuroprotective activity, first against oxidative stress-mediated toxicity and subsequently against HIV Tat and gp120-mediated neurodegeneration. Our preliminary studies showed that both BMD-101 and BMD-104 are comparably neuroprotective against these HIV protein toxins, with neuroprotective EC50 of 0.1-0.5 5M. Here we propose to further test and develop BMD-101 and BMD-104 as novel adjunctive therapeutic agents for neurological complications of HIV infection. The therapeutic potential of these compounds will be tested against various mechanisms of neuronal injury as well as its ability to prevent HIV replication. Our preliminary data show neuroprotective properties in in-vitro assays. Since both compounds successfully penetrate the BBB in neuroprotective quantities, we propose to evaluate them for neuroprotective proof of concept in two animal models of HIV protein-mediated neurodegeneration. Our hypothesis is that both compounds will protect human neurons from HIV Tat, gp120, ART and oxidative stress mediated neurodegeneration, and display neuroprotective efficacy in vivo in animal models of HAND. Additionally, our very preliminary data show that BMD-101 and 104 reduce HIV replication in vitro. Specific Aim 1) Characterize the bioactivity of BMD-101 and BMD-104 to facilitate neuroprotective drug development research for HAND (1.A) Determine efficacy and potency of BMD-101 and BMD-104 versus neurotoxic mechanisms relevant to the pathogenesis of HIV dementia (1.B) Effect of BMD-101 and BMD-104 on HIV-1 viral replication in lymphocytes and macrophages Specific Aim 2 Determine in vivo Neuroprotection with BMD-101 and BMD-104 in models of HAND ! PUBLIC HEALTH RELEVANCE: HIV/AIDS affects approximately 1.1 million adults and adolescents in the US, and is an important cause of disability. Highly active antiretroviral therapy (HAART) has increased life expectancy, but HIV infection can still lead to severe complications in the nervous system such as HIV-associated neurocognitive disorders (HAND) and sensory distal neuropathy (HIV-SN) for which there is currently no effective treatment. This research focuses on developing a new medication with potential cognition-enhancing, neuroprotective and antiretroviral properties that when used together with existing medications may more effectively treat the cognitive and functional impairments in HIV/AIDS.

描述（由申请人提供）：在艾滋病患者中引入和实施高度活跃的抗逆转录病毒疗法（HAART）减少了HIV病毒载量并导致预期寿命的增加，但是HIV感染仍然会导致神经系统中的严重并发症，例如HIV相关的神经认知疾病（与感官）和感觉疾病（手）和感觉疾病（Hand）和感官神经疗法（HIV-SN）。对于该患者人群，目前尚无辅助和神经保护治疗，但急需。在手上，神经元功能障碍主要是由涉及HIV蛋白和从HIV感染细胞释放的HIV蛋白和可溶性介质引起的氧化应激和兴奋性毒性的机制介导的。基于这些前提，我们为使用大鼠和人类原发性神经元培养物的神经保护剂开发了一种新型的神经毒性测定。通过这种神经毒性测定，我们评估了BMD-101和BMD-104的神经保护活性，首先是针对氧化应激介导的毒性，然后针对HIV TAT和GP120介导的神经变性。我们的初步研究表明，对这些HIV蛋白毒素的BMD-101和BMD-104均具有相当的神经保护性，神经保护EC50为0.1-0.5 5M。在这里，我们建议进一步测试和开发BMD-101和BMD-104作为HIV感染神经系统并发症的新型辅助治疗剂。这些化合物的治疗潜力将针对神经元损伤的各种机制及其预防HIV复制的能力进行测试。我们的初步数据显示了体外测定中的神经保护特性。由于两种化合物都成功地穿透了BBB的神经保护量，因此我们建议在HIV蛋白介导的神经变性的两种动物模型中对它们进行神经保护验证。我们的假设是，两种化合物都将保护人类神经元免受HIV TAT，GP120，ART和氧化应激介导的神经变性，并在动物模型中在体内显示神经保护功效。此外，我们非常初步的数据表明，BMD-101和104在体外减少HIV复制。具体目的1）表征BMD-101和BMD-104的生物活性以促进手动神经保护药物开发研究（1.A）（1.A）确定BMD-101和BMD-104与HIV dementia（1.b）bMD-104和BMD-1011和BMD-1001和BMD-1001和BMD-1001和BMD-1001和BMD-1001和BMD-1001和BMD-1001的功效和BMD-104与神经毒性机制的疗效和效率淋巴细胞和巨噬细胞特异性目标2在手模型中用BMD-101和BMD-104确定体内神经保护作用！ 公共卫生相关性：艾滋病毒/艾滋病在美国影响约110万成人和青少年，这是残疾的重要原因。高度活跃的抗逆转录病毒疗法（HAART）的预期寿命增加，但是HIV感染仍然会导致神经系统的严重并发症，例如与HIV相关的神经认知障碍（手）和感觉远端神经病（HIV-SN），目前尚无有效的治疗。这项研究重点是开发一种具有潜在认知增强，神经保护性和抗逆转录病毒特性的新药物，当与现有药物一起使用时，该药物可能会更有效地治疗HIV/AID中的认知和功能障碍。