Novel brain-penetrant fusion inhibitors for control of CNS infection.

用于控制中枢神经系统感染的新型脑渗透融合抑制剂。

• 批准号: 8300066
• 负责人: Matteo Porotto
• 金额: $ 19.17万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300066
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Adverse effects; Animal Model; Anti-Retroviral Agents; Antiretroviral resistance; Antiviral Agents; Binding; Biological Availability; Blood - brain barrier anatomy; Brain; CXCR4 Receptors; Cell membrane; Central Nervous System Infections; Chimeric Proteins; Cholesterol; Clinical; Clinical Trials; Complex; Development; Diffuse; Disease; Dominant-Negative Mutation; Dose; Drug Kinetics; Effectiveness; Encephalitis; Entropy; Environment; Feline Immunodeficiency Virus; Felis catus; Fuzeon; Generations; HIV; HIV Fusion Inhibitors; HIV Infections; Half-Life; Hendra Virus; Highly Active Antiretroviral Therapy; Human; In Vitro; Infection; Lead; Lipoproteins; Mediating; Medical; Membrane; Membrane Fusion; Membrane Microdomains; Modeling; Modification; Neuraxis; Neurocognitive; Neuropathogenesis; Para-Influenza Virus Type 3; Paramyxovirus; Patients; Penetration; Peptides; Pharmaceutical Preparations; Plasma; Prevalence; Process; Protein Binding; Protein Region; Proteins; Regimen; Reporting; Staging; Structure; Subfamily lentivirinae; T-20; Testing; Therapeutic; Therapeutic Uses; Translating; Transmembrane Domain; Validation; Viral; Viral Fusion Proteins; Virus; Virus Diseases; Virus Replication; base; drug modification; enthalpy; env Gene Products; feeding; improved; in vivo; inhibitor/antagonist; novel; peptide C34; prevent; research study; resistant strain; safety testing; treatment strategy

DESCRIPTION (provided by applicant): Infection of CNS by HIV can lead to encephalitis that presents clinically as HIV- associated dementia and HIV-associated neurocognitive disorders ("neuro-AIDS"). Despite the advent of HAART, at the late stage of the disease more than 11% of HIV patients suffer from HIV-associated dementia. Current antiretroviral drugs are ineffective at treating viral infection in the brain, because they cannot freely diffuse across the blood-brain barrier (BBB). Therefore, HIV viral replication persists in the CNS and continues to augment the neuropathogenesis process. The development of antivirals which can cross the BBB is therefore a critical unmet medical need. We propose a new strategy to prevent and treat HIV CNS infection, through application of the results of our recent discoveries. We found that attachment of a cholesterol group ("cholesterol tagging") to a peptide fusion inhibitor (FI) endows it with the ability to penetrate the brain. Use of peptide FI as HIV antivirals is a clinically validated strategy. However, the only FI in clinical use, (enfuvirtide, Fuzeon(R)), cannot penetrate the CNS. The use of cholesterol tagging for BBB penetration would be compounded by two additional advantages: (i) localization of the peptide in the lipid rafts where fusion activation occurs, resulting in dramatically increased antiviral potency, and (ii) binding to plasma lipoproteins, resulting in increased half-life in vivo. Accordingly, we recently described a cholesterol-tagged HIV peptide, which is the most potent FI reported to date, H100-fold more potent than enfuvirtide. We propose here to assess the potential of cholesterol-tagged FI to treat retroviral infection of the CNS, using feline Immunodeficiency Virus (FIV) as a unique and credible model for neuro-AIDS.

描述（由申请人提供）：HIV感染CNS可导致脑炎，临床表现为HIV相关痴呆和HIV相关神经认知障碍（“神经AIDS”）。尽管HAART的出现，在疾病的晚期，超过11%的HIV患者患有HIV相关性痴呆。目前的抗逆转录病毒药物在治疗大脑中的病毒感染方面是无效的，因为它们不能自由地扩散穿过血脑屏障（BBB）。因此，HIV病毒复制在CNS中持续存在，并继续增强神经发病过程。因此，开发能够穿过BBB的抗病毒药物是一个关键的未满足的医疗需求。我们提出了一个新的战略，以预防和治疗HIV中枢神经系统感染，通过应用我们最近的发现的结果。我们发现胆固醇基团（“胆固醇标记”）与肽融合抑制剂（FI）的连接赋予其穿透大脑的能力。使用肽FI作为HIV抗病毒药物是临床验证的策略。然而，临床使用的唯一FI（恩夫韦地、Fuzeon（R））无法穿透中枢神经系统。使用胆固醇标记进行BBB渗透还具有两个额外的优点：（i）肽定位在发生融合激活的脂筏中，导致抗病毒效力显着增加，以及（ii）与血浆脂蛋白结合，导致体内半衰期增加。因此，我们最近描述了一种胆固醇标记的HIV肽，这是迄今为止报道的最有效的FI，比恩夫韦肽有效100倍。我们建议在这里评估胆固醇标记的FI治疗CNS逆转录病毒感染的潜力，使用猫免疫缺陷病毒（FIV）作为神经艾滋病的独特和可信的模型。