Multivalent display of anthrax toxin inhibitors

炭疽芽孢杆菌产生一种毒素，可导致受感染个体的细胞死亡和死亡。即使细菌感染本身被抗生素控制，受感染的人也经常死亡，因为炭疽杆菌在体内产生的炭疽毒素（AT）与人体细胞结合，被内吞并杀死细胞。因此，为了有效治疗炭疽暴露，开发特异性抗毒素以防止AT与人体细胞结合是必要的。这是本计划奖助金的目标。J. Young和J. Collier小组发现并描述了AT与其细胞受体之间的相互作用。这项工作推动了新的基于肽的炭疽抗毒素的发现和开发（项目1和2）。本研究拟以植物病毒颗粒豇豆花叶病毒（CPMV）或昆虫病毒禽舍病毒（FHV）为展示平台，以多价形式展示抑制肽和可溶性AT受体蛋白（项目3-5）。这些多价平台将被生产出来，并在体内和体外测试其作为抗毒素的功效。这些病毒耐热耐酸，容易大量生产。这两种病毒都有很好的遗传、生化和结构特征，可以通过工程或化学修饰，在其表面显示外源免疫原性或抗毒素肽序列的多个拷贝。曼彻斯特小组（项目3）先前已经证明，通过在CPMV上多价展示抑制肽，可以有效地阻断病毒-细胞受体相互作用，无论是在体外还是在体内。利用这一令人兴奋的结果作为概念证明，我们将测试多价的假设

Bacillus anthracis produces a toxin that causes cell death and mortality in infected individuals. Even if the bacterial infection itself is controlled by antibiotics, an infected person often dies because the anthrax toxin (AT) produced in vivo by B. anthracis binds to human cells, is endocytosed, and kills the cells. Therefore development of specific antitoxins that prevent AT from binding to human cells is necessary for effectively treating anthrax exposure,. This is the goal of this Program Project grant. The groups of J. Young and J. Collier have discovered and characterized the interaction between AT and its cellular receptors. This work fuels the discovery and development of novel peptide-based anthrax anti-toxins (Projects 1 and 2). Here we propose to display the inhibitory peptides and soluble AT receptor-based proteins in a multivalent form using the plant virus particle cowpea mosaic virus (CPMV) or the insect virus Flock house virus (FHV) as display platforms (Projects 3-5). These multivalent platforms will be produced and tested for their efficacy as antitoxins both in vitro and in vivo. These viruses are heat and acid-stable and are easy to produce in large quantities. Both viruses have been very well characterized genetically, biochemically and structurally and can either be engineered, or chemically modified, to display multiple copies of foreign immunogenic or antitoxin peptide sequences on their surface. The Manchester group (project 3) has previously shown that a virus-cellular receptor interaction can be efficiently blocked, both in vitro and in vivo, by the multivalent display of an inhibitory peptide on CPMV. Using this exciting result as a proof of concept, we will test the hypothesis that multivalent display of AT inhibitory peptides on CPMV and FHV will lead to the creation of a panel of new and effective anthrax antitoxins and vaccine reagents.