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

描述（由申请人提供）：HIV感染中枢神经系统可导致脑炎，临床表现为HIV相关痴呆和HIV相关神经认知障碍（“神经艾滋病”）。尽管出现了HAART，但在疾病晚期，超过11%的艾滋病毒患者患有与艾滋病毒相关的痴呆。目前的抗逆转录病毒药物对治疗脑部病毒感染无效，因为它们不能自由扩散穿过血脑屏障（BBB）。因此，HIV病毒在中枢神经系统中持续复制，并继续增强神经发病过程。因此，开发能够穿过血脑屏障的抗病毒药物是一个尚未得到满足的关键医疗需求。我们提出了一种新的策略来预防和治疗艾滋病毒中枢神经系统感染，通过应用我们最近的发现的结果。我们发现，胆固醇基团（“胆固醇标签”）附着在肽融合抑制剂（FI）上，使其具有穿透大脑的能力。使用肽FI作为HIV抗病毒药物是一种临床验证的策略。然而，临床使用的唯一FI（恩福韦肽，Fuzeon(R)）不能穿透中枢神经系统。使用胆固醇标记来渗透血脑屏障将有两个额外的优势：(i)肽在脂筏中发生融合激活，从而显着提高抗病毒效力；（ii）与血浆脂蛋白结合，从而增加体内半衰期。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，比恩福韦肽的效力高100倍。我们在此建议评估胆固醇标记的FI治疗中枢神经系统逆转录病毒感染的潜力，使用猫免疫缺陷病毒（FIV）作为一种独特而可信的神经艾滋病模型。

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.