NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Virol. 2019 May 15;93(11). doi: 10.1128/JVI.02312-18. Print 2019 Jun 1.
HIV infection requires lifelong treatment with multiple antiretroviral drugs in a combination, which ultimately causes cumulative toxicities and drug resistance, thus necessitating the development of novel antiviral agents. We recently found that enfuvirtide (T-20)-based lipopeptides conjugated with fatty acids have dramatically increased and anti-HIV activities. Herein, a group of cholesterol-modified fusion inhibitors were characterized with significant findings. First, novel cholesterylated inhibitors, such as LP-83 and LP-86, showed the most potent activity in inhibiting divergent human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). Second, the cholesterylated inhibitors were highly active to inhibit T-20-resistant mutants that still conferred high resistance to the fatty acid derivatives. Third, the cholesterylated inhibitors had extremely potent activity to block HIV envelope (Env)-mediated cell-cell fusion, especially a truncated minimum lipopeptide (LP-95), showing a greatly increased potency relative to its inhibition on virus infection. Fourth, the cholesterylated inhibitors efficiently bound to both the cellular and viral membranes to exert their antiviral activities. Fifth, the cholesterylated inhibitors displayed low cytotoxicity and binding capacity with human serum albumin. Sixth, we further demonstrated that LP-83 exhibited extremely potent and long-lasting anti-HIV activity in rhesus monkeys. Taken together, the present results help our understanding on the mechanism of action of lipopeptide-based viral fusion inhibitors and facilitate the development of novel anti-HIV drugs. The peptide drug enfuvirtide (T-20) remains the only membrane fusion inhibitor available for treatment of viral infection, which is used in combination therapy of HIV-1 infection; however, it exhibits relatively low antiviral activity and a genetic barrier to inducing resistance, calling for the continuous development for novel anti-HIV agents. In this study, we report cholesterylated fusion inhibitors showing the most potent and broad anti-HIV activities to date. The new inhibitors have been comprehensively characterized for their modes of action and druggability, including small size, low cytotoxicity, binding ability to human serum albumin (HSA), and, especially, extremely potent and long-lasting antiviral activity in rhesus monkeys. Therefore, the present studies have provided new drug candidates for clinical development, which can also be used as tools to probe the mechanisms of viral entry and inhibition.
HIV 感染需要终身使用多种抗逆转录病毒药物联合治疗，这最终会导致累积毒性和耐药性，因此需要开发新的抗病毒药物。我们最近发现，基于 enfuvirtide（T-20）的脂肪酸缀合脂肽大大提高了抗 HIV 活性。在此，我们对一组胆固醇修饰的融合抑制剂进行了特征描述，发现了一些显著结果。首先，新型胆固醇化抑制剂，如 LP-83 和 LP-86，对不同的人免疫缺陷病毒 1（HIV-1）、HIV-2 和猴免疫缺陷病毒（SIV）显示出最强的抑制活性。其次，胆固醇化抑制剂对 T-20 耐药突变体也具有高度抑制活性，而这些突变体对脂肪酸衍生物仍具有高耐药性。第三，胆固醇化抑制剂对 HIV 包膜（Env）介导的细胞-细胞融合具有极强的阻断活性，特别是一种截断的最小脂肽（LP-95），其抑制病毒感染的效力大大提高。第四，胆固醇化抑制剂能够与细胞膜和病毒膜结合发挥抗病毒活性。第五，胆固醇化抑制剂与人血清白蛋白的结合能力低，细胞毒性低。第六，我们进一步证明 LP-83 在恒河猴中具有极强且持久的抗 HIV 活性。综上所述，本研究结果有助于我们理解基于脂肽的病毒融合抑制剂的作用机制，并促进新型抗 HIV 药物的开发。肽类药物 enfuvirtide（T-20）仍然是唯一可用于治疗病毒感染的膜融合抑制剂，用于 HIV-1 感染的联合治疗；然而，它的抗病毒活性相对较低，并且存在遗传屏障导致耐药性，因此需要不断开发新型抗 HIV 药物。在这项研究中，我们报告了迄今为止具有最强和最广泛抗 HIV 活性的胆固醇化融合抑制剂。这些新抑制剂的作用模式和可用药性已得到全面表征，包括体积小、细胞毒性低、与人血清白蛋白（HSA）结合能力强，特别是在恒河猴中具有极强且持久的抗病毒活性。因此，本研究为临床开发提供了新的候选药物，也可作为研究病毒进入和抑制机制的工具。
