美国伦斯勒理工学院的研究人员开发了一种新型抗体，每个新型抗体可以绑定多达10个目标蛋白，证实其能够异常有效地防止与阿尔茨海默氏症、帕金森氏病以及2型糖尿病相关的有毒蛋白颗粒形成。相关研究发表在《美国科学院院刊》（PNAS）杂志上。
新型抗体强效阻止神经疾病中的毒蛋白形成
蛋白质不适当聚集形成颗粒，损害大脑（阿尔茨海默氏症和帕金森氏病）和胰腺（2型糖尿病）中的细胞，与这些破坏性疾病的发生密切相关。抗体，这一免疫系统常用来对抗细菌和病毒等外来入侵物的蛋白，现在被视作是阻止有毒蛋白质颗粒形成的一种有前景的武器。然而常规的抗体存在一项限制，其无法达到完全抑制有毒蛋白颗粒形成所需的高浓度。
为了解决这个问题，伦斯勒理工学院化学与生物工程系助理教授彼得•泰斯特带领的研究小组开发出一种制造更强效抗体的新方法。每个常规抗体通常只能绑定到1个或2个目标蛋白，相比之下，每个新型抗体可以绑定多达10个目标蛋白，效力的增强使得新型抗体在非常低的浓度下也能防止毒性蛋白斑块的形成。这是迈向开发对抗阿尔茨海默病和帕金森病等疾病的新疗法的重要一步。
Tessier 说：“获得能够进入大脑的抗体是极其困难的事情。注入到患者血液中的抗体，只有不到5%能进入大脑。因此，我们需要构建出尽可能有效的抗体，以确保进入大脑的小部分完全能够阻止与阿尔茨海默氏症和帕金森氏病有关的毒性蛋白质颗粒形成。我们提出的抗体抑制剂新设计策略利用了引起有毒颗粒形成的分子相互作用，由此生成的抗体相比免疫系统产生的抗体具有更强的抑制效力。”
Tessier的研究代表了一种生成治疗性抗体的新途径。目前，大多数抗体都是利用啮齿动物免疫系统获得。向小鼠注入某一靶蛋白，例如阿尔茨海默氏症蛋白，动物免疫系统就会产生这一靶蛋白的特异性抗体。Tessier的方法完全不同，它是依赖于合理的设计方法，基于靶蛋白的性质来生成抗体。
Rational design of potent domain antibody inhibitors of amyloid fibril assembly
Ali Reza A. Ladiwala,Moumita Bhattacharya,Joseph M. Perchiacca,Ping Cao,Daniel P. Raleigh,Andisheh Abedini,Ann Marie Schmidt,Jobin Varkey,Ralf Langen, andPeter M. Tessier
Antibodies hold significant potential for inhibiting toxic protein aggregation associated with conformational disorders such as Alzheimer’s and Huntington’s diseases. However, near-stoichiometric 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 gammabody:monomer 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.
文献链接：Rational design of potent domain antibody inhibitors of amyloid fibril assembly
