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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mechanism by which the lectin actinohivin blocks HIV infection of target cells
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Mechanism by which the lectin actinohivin blocks HIV infection of target cells

机译：凝集素放线菌素阻断HIV感染靶细胞的机制

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摘要

Various lectins have attracted attention as potential microbicides to prevent HIV transmission. Their capacity to bind glycoproteins has been suggested as a means to block HIV binding and entry into susceptible cells. The previously undescribed lectin actinohivin (AH), isolated by us from an actinomycete, exhibits potent in vitro anti-HIV activity by binding to high-mannose (Man) type glycans (HMTGs) of gp120, an envelope glycoprotein of HIV. AH contains 114 aa and consists of three segments, all of which need to show high affinity to gp120 for the anti-HIV characteristic. To generate the needed mechanistic understanding of AH binding to HIV in anticipation of seeking approval for human testing as a microbi-cide, we have used multiple molecular tools to characterize it. AH showed a weak affinity to Manα(1-2)Man, Manα(1-2)Manα(1-2)Man, of HMTG (Man8 or Man9) or RNase B (which has a single HMTG), but exhibited a strong and highly specific affinity (K_d= 3.4 × 10~(-8) M) to gp120 of HIV, which contains multiple Man8 and/or Man9 units. We have compared AH to an alternative lectin, cyanovirin-N, which did not display similar levels of discrimination between high- and low-density HMTGs. X-ray crystal analysis of AH revealed a 3D structure containing three sugar-binding pockets. Thus, the strong specific affinity of AH to gp120 is considered to be due to multivalent interaction of the three sugar-binding pockets with three HMTGs of gp120 via the "cluster effect" of lectin. Thus, AH is a good candidate for investigation as a safe microbicide to help prevent HIV transmission.
机译：各种凝集素作为预防HIV传播的潜在杀菌剂已引起关注。已经提出它们结合糖蛋白的能力是阻断HIV结合和进入易感细胞的一种手段。我们从放线菌中分离出的先前未描述的凝集素放线菌素（AH），通过与gp120（一种HIV包膜糖蛋白）的高甘露糖（Man）型聚糖（HMTG）结合，表现出强大的体外抗HIV活性。 AH包含114个氨基酸，由三个部分组成，所有这些部分都需要显示出对gp120的高亲和力才能具有抗HIV的特性。为了对AH与HIV的结合产生必要的机械理解，以期寻求获得批准作为微生物杀菌剂进行人体测试，我们使用了多种分子工具对其进行表征。 AH对HMTG（Man8或Man9）或RNase B（具有一个HMTG）的Manα（1-2）Man，Manα（1-2）Manα（1-2）Man弱亲和力，但表现出很强的亲和力对gp120的HIV gp120具有高度特异性（K_d = 3.4×10〜（-8）M），其中含有多个Man8和/或Man9单位。我们将AH与另一种凝集素cyanovirin-N进行了比较，后者在高密度和低密度HMTG之间没有相似的区分度。 AH的X射线晶体分析显示3D结构包含三个糖结合袋。因此，AH对gp120的强特异性亲和力被认为是由于三个糖结合袋与gp120的三个HMTG经由凝集素的“簇效应”的多价相互作用。因此，AH是一种安全的杀菌剂，可以帮助防止HIV传播，因此是进行调查的良好选择。

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  • 作者

    Haruo Tanaka; Harumi Chiba; Junji lnokoshi; Atsushi Kuno; Takahiro Sugai; Atsushi Takahashi; Yukishige lto; Masaru Tsunoda; Kaoru Suzuki; Akio Takenaka; Takeshi Sekiguchi; Hideaki Umeyama; Jun Hirabayashi; Satoshi Omura;

  • 作者单位

    Faculty of Pharmacy and College of Science and Engineering, Iwaki Meisei University, Iwaki, Fukushima 970-8551, Japan;

    School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan;

    School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan;

    Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan;

    School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan;

    Faculty of Pharmacy and College of Science and Engineering, Iwaki Meisei University, Iwaki, Fukushima 970-8551, Japan;

    Synthetic Cellular Chemistry Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan;

    Faculty of Pharmacy and College of Science and Engineering, Iwaki Meisei University, Iwaki, Fukushima 970-8551, Japan;

    Faculty of Pharmacy and College of Science and Engineering, Iwaki Meisei University, Iwaki, Fukushima 970-8551, Japan;

    Faculty of Pharmacy and College of Science and Engineering, Iwaki Meisei University, Iwaki, Fukushima 970-8551, Japan Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8501, Japan;

    Faculty of Pharmacy and College of Science and Engineering, Iwaki Meisei University, Iwaki, Fukushima 970-8551, Japan;

    School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan;

    Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan;

    Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo 108-8641, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    action mechanism; anti-HIV; gp120; high-mannose type glycan; cyanovirin-N;

    机译：动作机制抗艾滋病毒gp120;高甘露糖型聚糖;氰维N;

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