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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phage escape libraries for checkmate analysis
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Phage escape libraries for checkmate analysis

机译：噬菌体逃逸库，用于将死分析

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Ligand-binding epitopes of proteins can mutate rapidly, as shown by viral mutations that lead to escape from neutralizing antibodies. We have undertaken to recreate in vitro the evolutionary competition between viral mutations that allow escape from antibody binding and host mutations that generate new neutralizing antibodies to the mutated viral antigen. To examine this vital race, we describe a phage-based method that allows rapid analysis of molecules that perturb the binding of proteins to their ligands. Because the system can amplify by replication, single-molecule sensitivity can be achieved. When combinatorial protein or small-molecule libraries are studied, large numbers of binding events can be analyzed simultaneously. Such libraries may be used in a sequential phage escape format, where cycles of phage binding and release of mutants are driven by antibodies or small molecules and the difficulty of escape increases at each cycle. Ultimately, the sequencing of the viral mutants allows annotation of the allowed trajectory of escape. Likewise, sequencing of the antibody pertur-bants charts the chemistry of the immune system response to the viral challenge. We have termed such analysis of competing mutations a "checkmate analysis." When viral systems are studied, a checkmate analysis allows experimental evaluation of the evolutionary contest between viruses and the immune system and may predict which antibodies and small-molecule ligands should be generated in anticipation of viral mutations before these mutations create viral epidemics.
机译：蛋白质的配体结合表位可以快速突变，如病毒突变所示，该突变导致从中和抗体中逃逸。我们已承诺在体外重建病毒突变（允许逃脱抗体结合）与宿主突变（产生针对突变病毒抗原的新中和抗体）之间的进化竞争。为了检查这一重要种族，我们描述了一种基于噬菌体的方法，该方法可以快速分析扰乱蛋白质与其配体结合的分子。因为系统可以通过复制进行扩增，所以可以实现单分子敏感性。当研究组合蛋白或小分子文库时，可以同时分析大量的结合事件。这样的文库可以按顺序的噬菌体逃逸形式使用，其中噬菌体结合和突变体释放的周期由抗体或小分子驱动，并且逃逸的难度在每个周期增加。最终，病毒突变体的测序允许注释所允许的逃逸轨迹。同样，抗体扰动剂的测序可以绘制免疫系统对病毒激发反应的化学反应。我们称这种对竞争性突变的分析称为“将死分析”。在研究病毒系统时，将检查分析可以对病毒和免疫系统之间的进化竞争进行实验评估，并可以预测在预期病毒突变之前应产生哪些抗体和小分子配体，然后这些突变会导致病毒流行。

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