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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Rational design of potent domain antibody inhibitors of amyloid fibril assembly
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Rational design of potent domain antibody inhibitors of amyloid fibril assembly

机译：淀粉样蛋白原纤维组装的有效域抗体抑制剂的合理设计

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摘要

Antibodies hold significant potential for inhibiting toxic protein aggregation associated with conformational disorders such as Alzheimer's and Huntington's diseases. However, near-stoichio-metric antibody concentrations are typically required to completely inhibit protein aggregation. We posited that the molecular interactions mediating amyloid fibril formation could be harnessed to generate antibodies with potent antiaggregation. Here we report that grafting small amyloidogenic peptides (6-10 residues) into the complementarity-determining regions of a single-domain (VH) antibody yields potent domain antibody inhibitors of amyloid formation. Grafted AMyloid-Motif AntiBODIES (gammabodies) presenting hydrophobic peptides from Aβ (Alzheimer's disease), α-Synuclein (Parkinson's disease), and islet amyloid polypeptide (type 2 diabetes) inhibit fibril assembly of each corresponding polypeptide at low substoichiometric concentrations (1:10 gamma-bodyimonomer molar ratio). In contrast, sequence- and conformation-specific antibodies that were obtained via immunization are unable to prevent fibrillization at the same substoichiometric concentrations. Gammabodies prevent amyloid formation by converting monomers and/or fibrillar intermediates into small complexes that are unstructured and benign. We expect that our antibody design approach-which eliminates the need for immunization or screening to identify sequence-specific domain antibody inhibitors-can be readily extended to generate potent aggregation inhibitors of other amyloidogenic polypeptides linked to human disease.
机译：抗体具有抑制与构象性疾病如阿尔茨海默氏病和亨廷顿氏病有关的毒性蛋白质聚集的巨大潜力。但是，通常需要接近化学计量的抗体浓度才能完全抑制蛋白质聚集。我们认为介导淀粉样蛋白原纤维形成的分子相互作用可以利用产生具有有效抗聚集作用的抗体。在这里我们报告说，将小淀粉样蛋白肽（6-10个残基）嫁接到单结构域（VH）抗体的互补决定区中，可产生有效的淀粉样蛋白结构域抗体抑制剂。呈现Aβ（阿尔茨海默氏病），α-突触核蛋白（帕金森氏病）和胰岛淀粉样多肽（2型糖尿病）疏水肽的嫁接淀粉样蛋白母体抗体（γ抗体）在低化学计量比浓度（1:10）下抑制每种相应多肽的原纤维组装γ-bodyimonomer摩尔比）。相反，通过免疫获得的序列特异性和构象特异性抗体在相同的亚化学计量浓度下不能防止原纤维形成。 γ抗体通过将单体和/或原纤维中间体转化为无结构且良性的小复合物来防止淀粉样蛋白形成。我们希望我们的抗体设计方法（无需进行免疫或筛选来鉴定序列特异性域抗体抑制剂）可以很容易地扩展为生成与人类疾病相关的其他淀粉样蛋白多肽的有效聚集抑制剂。

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    Ali Reza A. Ladiwala; Moumita Bhattacharya; Joseph M. Perchiacca; Ping Cao; Daniel P. Raleigh; Andisheh Abedini; Ann Marie Schmidt; Jobin Varkey; Ralf Langen; Peter M. Tessier;

  • 作者单位

    Center for Biotechnology and Interdisciplinary Studies, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180;

    Center for Biotechnology and Interdisciplinary Studies, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180;

    Center for Biotechnology and Interdisciplinary Studies, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180;

    Department of Chemistry, Stony Brook University of New York, Stony Brook, NY 11794;

    Department of Chemistry, Stony Brook University of New York, Stony Brook, NY 11794;

    Diabetes Research Program, New York University School of Medicine, New York, NY 10016;

    Diabetes Research Program, New York University School of Medicine, New York, NY 10016;

    Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033;

    Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033;

    Center for Biotechnology and Interdisciplinary Studies, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180;

  • 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

    beta-amyloid; misfolding; protein design; IAPP;

    机译：β-淀粉样蛋白错叠蛋白质设计;行动计划;

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