Structure-based design of decoy chemokines as a way to explore the pharmacological potential of glycosaminoglycans
Structure-based design of decoy chemokines as a way to explore the pharmacological potential of glycosaminoglycans
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DOI：
10.1111/j.1476-5381.2012.02089.x
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发表时间：
2012-11-01
影响因子：
7.3
通讯作者：
Kungl, Andreas J.
中科院分区：
文献类型：
--
作者：
Adage, Tiziana;Piccinini, Anna-Maria;Kungl, Andreas J.
糖胺聚糖（Glycosaminoglycans，GAG）是一类高度带负电荷的、无分支的、O-连接的多糖，其参与许多疾病。它们作为细胞表面上的蛋白质结合基质的作用早已被认识到，但干扰蛋白质GAG相互作用的治疗方法受到限制，一方面是由于GAG的复杂化学性质，另一方面是由于缺乏针对GAG的特异性抗体。我们已经开发了一种蛋白质工程平台（所谓的CellJammer（R）技术），该平台使我们能够将更高的GAG结合亲和力引入野生型GAG结合蛋白，并将其与受损的生物学受体结合功能联合收割机结合。趋化因子是典型的GAG结合蛋白，在这里，我们提出了我们的CellJammer技术应用于这些促炎蛋白的几个选择的结果。概述了我们的铅诱饵蛋白，PA 401，这是一个CXCL 8为基础的突变蛋白与GAG结合亲和力增加和减少CXCR 1/2的结合和激活。我们的CCL 2和CCL 5程序的主要结果也进行了总结，并提出了这些诱饵蛋白的临床应用的潜力。
Glycosaminoglycans (GAGs) are a class of highly negatively charged, unbranched, O-linked polysaccharides that are involved in many diseases. Their role as a protein-binding matrix on cell surfaces has long been recognized, but therapeutic approaches to interfere with proteinGAG interactions have been limited due to the complex chemistry of GAGs, on one hand, and due to the lack of specific antibodies against GAGs, on the other hand. We have developed a protein engineering platform (the so-called CellJammer (R) technology), which enables us to introduce higher GAG-binding affinity into wild-type GAG-binding proteins and to combine this with impaired biological, receptor-binding function. Chemokines are among the prototypic GAG-binding proteins and here we present selected results of our CellJammer technology applied to several of these proinflammatory proteins. An overview is given of our lead decoy protein, PA401, which is a CXCL8-based mutant protein with increased GAG-binding affinity and decreased CXCR1/2 binding and activation. Major results from our CCL2 and CCL5 programmes are also summarized and the potential for clinical application of these decoy proteins is presented.