Mechanistic Insight into Antiretroviral Potency of 2′-Deoxy-2′-β-fluoro-4′-azidocytidine (FNC) with a Long-Lasting Effect on HIV-1 Prevention
Mechanistic Insight into Antiretroviral Potency of 2′-Deoxy-2′-β-fluoro-4′-azidocytidine (FNC) with a Long-Lasting Effect on HIV-1 Prevention
复制标题
2'-脱氧-2'-β-氟-4'-叠氮胞苷 (FNC) 的抗逆转录病毒效力机制洞察，对 HIV-1 预防具有持久作用
DOI：
10.1021/acs.jmedchem.0c00940
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发表时间：
2020-08-13
影响因子：
7.3
通讯作者：
Chang, Junbiao
中科院分区：
文献类型：
--
作者：
Sun, Li;Peng, Youmei;Chang, Junbiao
在临床前和I期和II期临床研究中，2 '-脱氧-2'-β-氟-4 '-叠氮胞苷（FNC）显示出对HIV-1感染的强效和持久的抑制作用。为了研究其作用机制，我们将其与已有文献报道的拉米夫定（3 TC）进行了比较。药代动力学研究表明，FNC三磷酸盐在外周血单个核细胞中的细胞内滞留时间明显长于3 TC三磷酸盐。FNC选择性地进入并保留在HIV靶细胞中，在那里它发挥长期预防HIV-1感染的作用。除了抑制HIV-1逆转录外，FNC还恢复了接受FNC治疗的HIV-1患者的CD 4（+）T细胞中A3 G的表达。FNC与Vif-E3泛素连接酶复合物结合，使A3 G能够避免Vif诱导的泛素化和降解。这些数据揭示了FNC的上级抗HIV效力和持久作用的机制。我们的研究结果还表明，FNC作为一种持久的暴露前预防剂，能够预防HIV感染的潜在临床应用。
In preclinical and phase I and II clinical studies, 2'-deoxy-2'-beta-fluoro-4'-azidocytidine (FNC) displays a potent and long-lasting inhibition of HIV-1 infection. To investigate its mechanism of action, we compared it with the well-documented lamivudine (3TC). Pharmacokinetic studies revealed that the intracellular retention of FNC triphosphate in peripheral blood mononuclear cells was markedly longer than that of the 3TC triphosphate. FNC selectively enters and is retained in HIV target cells, where it exerts long-lasting prevention of HIV-1 infection. In addition to inhibition of HIV-1 reverse transcription, FNC also restores A3G expression in CD4(+) T cells in FNC-treated HIV-1 patients. FNC binds to the Vif-E3 ubiquitin ligase complex, enabling A3G to avoid Vif-induced ubiquitination and degradation. These data reveal the mechanisms underlying the superior anti-HIV potency and long-lasting action of FNC. Our results also suggest a potential clinical application of FNC as a long-lasting pre-exposure prophylactic agent capable of preventing HIV infection.