Lindsley F Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
Viruses. 2013 Jan 11;5(1):127-49. doi: 10.3390/v5010127.
The hydrophobic pocket in the HIV-1 gp41 N-terminal heptad repeat (NHR) domain plays an important role in viral fusion and entry into the host cell, and serves as an attractive target for development of HIV-1 fusion/entry inhibitors. The peptide anti-HIV drug targeting gp41 NHR, T-20 (generic name: enfuvirtide; brand name: Fuzeon), was approved by the U.S. FDA in 2003 as the first HIV fusion/entry inhibitor for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, because T20 lacks the pocket-binding domain (PBD), it exhibits low anti-HIV-1 activity and short half-life. Therefore, several next-generation HIV fusion inhibitory peptides with PBD have been developed. They possess longer half-life and more potent antiviral activity against a broad spectrum of HIV-1 strains, including the T-20-resistant variants. Nonetheless, the clinical application of these peptides is still limited by the lack of oral availability and the high cost of production. Thus, development of small molecule compounds targeting the gp41 pocket with oral availability has been promoted. This review describes the main approaches for identification of HIV fusion/entry inhibitors targeting the gp41 pocket and summarizes the latest progress in developing these inhibitors as a new class of anti-HIV drugs.
HIV-1 gp41 N 端七肽重复（NHR）结构域中的疏水性口袋在病毒融合和进入宿主细胞中起着重要作用，是开发 HIV-1 融合/进入抑制剂的有吸引力的靶标。靶向 gp41 NHR 的肽类抗 HIV 药物 T-20（通用名：恩夫韦肽；商品名：Fuzeon）于 2003 年获得美国 FDA 批准，成为第一种用于治疗对现有抗逆转录病毒药物无反应的 HIV/AIDS 患者的 HIV 融合/进入抑制剂。然而，由于 T20 缺乏口袋结合域（PBD），其抗 HIV-1 活性较低，半衰期较短。因此，已经开发出几种具有 PBD 的下一代 HIV 融合抑制肽。它们具有更长的半衰期和对广泛的 HIV-1 株更有效的抗病毒活性，包括对 T-20 耐药的变异株。尽管如此，这些肽的临床应用仍然受到口服可用性和生产成本高的限制。因此，针对具有口服可用性的 gp41 口袋的小分子化合物的开发得到了推动。本文综述了鉴定靶向 gp41 口袋的 HIV 融合/进入抑制剂的主要方法，并总结了开发这些抑制剂作为一类新型抗 HIV 药物的最新进展。
