结构导向的抗原工程产生适合预防肺炎球菌病的肺炎球菌溶血素突变体。
Structure-guided antigen engineering yields pneumolysin mutants suitable for vaccination against pneumococcal disease.
机构信息
sanofi pasteur, Toronto, Ontario M2R 3T4, Canada.
出版信息
J Biol Chem. 2011 Apr 8;286(14):12133-40. doi: 10.1074/jbc.M110.191148. Epub 2011 Feb 4.
Abstract
Pneumolysin (PLY) is a cholesterol-binding, pore-forming protein toxin. It is an important virulence factor of Streptococcus pneumoniae and a key vaccine target against pneumococcal disease. We report a systematic structure-driven approach that solves a long-standing problem for vaccine development in this field: detoxification of PLY with retention of its antigenic integrity. Using three conformational restraint techniques, we rationally designed variants of PLY that lack hemolytic activity and yet induce neutralizing antibodies against the wild-type toxin. These results represent a key milestone toward a broad-spectrum protein-based pneumococcal vaccine and illustrate the value of structural knowledge in formulating effective strategies for antigen optimization.
摘要
肺炎球菌溶血素（PLY）是一种胆固醇结合、形成孔的蛋白毒素。它是肺炎链球菌的重要毒力因子，也是针对肺炎球菌病的关键疫苗靶点。我们报告了一种系统的结构驱动方法，该方法解决了该领域疫苗开发中的一个长期存在的问题：在保持 PLY 抗原完整性的同时，对其进行解毒。使用三种构象约束技术，我们合理设计了缺乏溶血活性但能诱导针对野生型毒素的中和抗体的 PLY 变体。这些结果代表了朝着广谱基于蛋白质的肺炎球菌疫苗迈出的重要一步，并说明了结构知识在制定有效的抗原优化策略方面的价值。
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