Chong Huihui, Xue Jing, Xiong Shengwen, Cong Zhe, Ding Xiaohui, Zhu Yuanmei, Liu Zixuan, Chen Ting, Feng Yifan, He Lei, Guo Yan, Wei Qiang, Zhou Yusen, Qin Chuan, He Yuxian
MOH 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. 2017 May 12;91(11). doi: 10.1128/JVI.00288-17. Print 2017 Jun 1.
Peptides derived from the C-terminal heptad repeat (CHR) region of the human immunodeficiency virus type 1 (HIV-1) fusogenic protein gp41 are potent viral entry inhibitors, and currently, enfuvirtide (T-20) is the only one approved for clinical use; however, emerging drug resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, an HIV-2 sequence, intrahelical salt bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad, and long-lasting antiviral activity. In studies, LP-19 efficiently inhibited HIV-1-, HIV-2-, and simian immunodeficiency virus (SIV)-mediated cell fusion, viral entry, and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and an extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced viral loads to undetectable levels in acutely and chronically simian-human immunodeficiency virus (SHIV)-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target. The peptide drug T-20 is the only viral fusion inhibitor in the clinic, which is used for combination therapy of HIV-1 infection; however, it requires a high dosage and easily induces drug resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short-lipopeptide-based fusion inhibitor, termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity against HIV-1, HIV-2, and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and an extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical use.
源自人类免疫缺陷病毒1型（HIV-1）融合蛋白gp41 C末端七肽重复序列（CHR）区域的肽是有效的病毒进入抑制剂，目前，恩夫韦肽（T-20）是唯一获批用于临床的此类药物；然而，新出现的耐药性在很大程度上限制了其疗效。在本研究中，我们通过整合多种设计策略，包括N末端M-T钩结构、HIV-2序列、螺旋内盐桥和膜锚定脂质尾，生成了一种新型脂肽抑制剂，命名为LP-19。LP-19表现出稳定的结合亲和力以及高效、广泛和持久的抗病毒活性。在研究中，LP-19有效抑制HIV-1、HIV-2和猴免疫缺陷病毒（SIV）介导的细胞融合、病毒进入和感染，并且对原发性HIV-1分离株和抑制剂耐药突变体的不同亚型具有高活性。研究表明，LP-19在恒河猴中表现出显著增强的抗HIV活性和延长的半衰期。在短期单药治疗中，LP-19可将急性和慢性感染猿猴-人类免疫缺陷病毒（SHIV）的猴子的病毒载量降低到检测不到的水平。因此，本研究提供了一种用于临床开发的理想HIV-1/2融合抑制剂，并强调了病毒融合步骤作为药物靶点的重要性。肽药物T-20是临床上唯一的病毒融合抑制剂，用于HIV-1感染的联合治疗；然而，它需要高剂量且容易诱导耐药性，因此需要一种药学特性显著改善的新药。在此，我们开发了一种基于短脂肽的融合抑制剂，称为LP-19，其主要靶向保守的gp41口袋位点，并对HIV-1、HIV-2甚至SIV分离株表现出高效抑制活性。LP-19在恒河猴中表现出显著增强的抗病毒活性和延长的半衰期，并且在感染SHIV的猴子中具有有效的治疗效果，突出了其作为临床使用的新型病毒融合抑制剂的高潜力。
