Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor
Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor
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DOI：
10.1074/jbc.m800200200
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发表时间：
2008-04-25
影响因子：
4.8
通讯作者：
Zhang, Linqi
中科院分区：
文献类型：
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作者：
He, Yuxian;Xiao, Yonghong;Zhang, Linqi
恩福韦肽(T20)是第一个也是唯一一个被批准临床使用的HIV-1融合抑制剂，但它容易产生耐药性，限制了其实际应用。基于HIV-1gp41融合核心构象的三维结构，设计了一种新型的抗人免疫缺陷病毒多肽，命名为西夫韦肽。在这里，我们报告了它的体外抗HIV效力，它的作用机制，以及Ia期临床研究的结果。我们证明，西夫韦肽以剂量依赖的方式抑制HIV-1介导的细胞-细胞融合，并对来自R5或X4表型的多种基因型的原代和实验室适应的HIV-1分离株的感染显示出很高的效力。值得注意的是，西夫韦肽对T20耐药株也非常有效。与T20不同的是，西夫韦肽能以显性负性方式有效地阻断六股螺旋束的形成。这些结果提示西夫韦肽的作用机制与T20不同。西夫韦肽(FS0101)在60名健康人中的Ia期临床研究显示良好的安全性、耐受性和药代动力学特征。单次给药方案(5，10，20，30和40毫克)每天在腹部部位皮下注射一次，耐受性良好，没有严重的不良反应。单次给药和多次给药的药代动力学研究表明，西夫韦肽的半衰期分别为20.0±8.6h和26.0±7.9h。综上所述，西夫韦肽有可能成为一种理想的融合抑制剂，用于治疗艾滋病毒/艾滋病患者，包括那些携带对T20耐药的HIV-1毒株的患者。
Enfuvirtide (T20) is the first and only HIV-1 fusion inhibitor approved for clinical use, but it can easily induce drug resistance limiting its practical application. A novel anti-HIV peptide, termed sifuvirtide, was designed based on the three-dimensional structure of the HIV-1 gp41 fusogenic core conformation. Here we report its in vitro anti-HIV potency, its mechanism of action, as well as the results from Phase Ia clinical studies. We demonstrated that sifuvirtide inhibited HIV-1-mediated cell-cell fusion in a dose-dependent manner and exhibited high potency against infections by a wide range of primary and laboratory-adapted HIV-1 isolates from multiple genotypes with R5 or X4 phenotypes. Notably, sifuvirtide was also highly effective against T20-resistant strains. Unlike T20, sifuvirtide could efficiently block six-helix bundle formation in a dominant negative fashion. These results suggest that sifuvirtide has a different mechanism of action from that of T20. Phase Ia clinical studies of sifuvirtide (FS0101) in 60 healthy individuals demonstrated good safety, tolerability, and pharmacokinetic profiles. A single dose regimen( 5,10,20,30, and 40 mg) by subcutaneous injection once daily at abdominal sites was well tolerated without serious adverse events. Pharmacokinetic studies of single and multiple administration of sifuvirtide showed that its decay half-lives were 20.0 +/- 8.6 h and 26.0 +/- 7.9h, respectively. In summary, sifuvirtide has potential to become an ideal fusion inhibitor for treatment of HIV/AIDS patients, including those with HIV-1 strains resistant to T20.