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学科主题: 临床医学
题名:
Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor
作者: He, Yuxian1,2,3; Xiao, Yonghong4; Song, Haifeng5; Liang, Qing6; Ju, Dan6; Chen, Xin6; Lu, Hong1; Jing, Weiguo1; Jiang, Shibo1; Zhang, Linqi2,3,7
刊名: JOURNAL OF BIOLOGICAL CHEMISTRY
发表日期: 2008-04-25
DOI: 10.1074/jbc.M800200200
卷: 283, 期:17, 页:11126-11134
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology
研究领域[WOS]: Biochemistry & Molecular Biology
关键词[WOS]: VIRUS TYPE-1 INFECTION ; GCN4 LEUCINE-ZIPPER ; ENTRY INHIBITORS ; MEMBRANE-FUSION ; COILED-COIL ; GP41 CORE ; ENVELOPE GLYCOPROTEINS ; ATOMIC-STRUCTURE ; SALT BRIDGES ; PEPTIDES
英文摘要:

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.

语种: 英语
WOS记录号: WOS:000255067400008
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/60016
Appears in Collections:北京大学第一临床医学院_临床药理研究所_期刊论文

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作者单位: 1.New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10021 USA
2.FusoGen Pharmaceut Inc, Beijing 100016, Peoples R China
3.Chinese Acad Med Sci, Inst Pathogen Biol, AIDS Res Ctr, Beijing 100730, Peoples R China
4.Peking Union Med Coll, Beijing 100730, Peoples R China
5.Peking Univ, Inst Clin Pharmacol, Beijing 100083, Peoples R China
6.Acad Mil Med Sci, Beijing Inst Radiat Med, Beijing 100850, Peoples R China
7.Tsinghua Univ, Comprehens AIDS Res Ctr, Beijing 100084, Peoples R China

Recommended Citation:
He, Yuxian,Xiao, Yonghong,Song, Haifeng,et al. Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2008,283(17):11126-11134.
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