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

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（恩夫韦肽，Fuzeon（R））不能渗透CNS。使用胆固醇标记用于BBB渗透将由两个额外的优点复合：（i）肽在发生融合活化的脂筏中的定位，导致显著增加的抗病毒效力，和（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。 公共卫生相关性：在艾滋病毒感染的晚期，高达11%的患者发展为艾滋病毒相关的痴呆和艾滋病毒相关的神经认知障碍。目前的药物在减少病毒复制方面非常有效，但不能治疗大脑中的感染，因为它们不能自由扩散穿过血脑屏障（BBB）。因此，病毒在中枢神经系统（CNS）中持续的低水平复制继续助长神经发病过程。因此，开发能够穿透BBB的抗病毒药物是一个关键的未满足的医疗需求。我们提出了一种策略，通过血脑屏障递送一种抗病毒药物--类似于已经在临床使用的药物（恩夫韦肽，Fuzeon（R））--以阻断CNS中的HIV感染。

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. PUBLIC HEALTH RELEVANCE: At the late stage of HIV infection, as high as 11% of patients develop HIV-associated dementia and HIV- associated neurocognitive disorders. Current drugs, which are highly effective in reducing viral replication, cannot treat infection in the brain, because they cannot freely diffuse across the blood-brain barrier (BBB). Persistent, low level replication of the virus in central nervous system (CNS) thus continues to feed the neuropathogenesis process. The development of antivirals which can penetrate the BBB is therefore a critical unmet medical need. We propose a strategy to deliver an antiviral drug - similar to one already in clinical use (enfuvirtide, Fuzeon(R)) - across the BBB to block HIV infection in the CNS.