Sequence-independent Control of Peptide Conformation in Liposomal Vaccines for Targeting Protein Misfolding Diseases
Sequence-independent Control of Peptide Conformation in Liposomal Vaccines for Targeting Protein Misfolding Diseases
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DOI：
10.1074/jbc.m110.186338
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发表时间：
2011-04-22
影响因子：
4.8
通讯作者：
Muhs, Andreas
中科院分区：
文献类型：
--
作者：
Hickman, David T.;Lopez-Deber, Maria Pilar;Muhs, Andreas
模拟与病理相关的靶表位构象的合成肽免疫原为精确控制免疫反应的特异性提供了可能性。在这里，我们使用一组多肽进行构象分析，以研究整合到脂质体双层中时控制其构象的关键参数。这些结果表明，多肽的脂化模式、脂质锚链长度和脂质体表面电荷都显著改变了多肽的构象。多肽聚集也可以通过添加不同的小分子β-折叠破碎剂来调节脂质体后的组装。用含有β-折叠聚集脂肽(Palm1-15)的模型脂质体疫苗免疫小鼠和猴子，可诱导多克隆抗体，该抗体可比单体或非病理性天然蛋白特异性地识别β-折叠多聚体。脂质体结合的具有特定构象的多肽免疫原的合理设计为生产针对一系列蛋白质错误折叠疾病的疫苗打开了可能性，例如阿尔茨海默病。
Synthetic peptide immunogens that mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter peptide conformation. Peptide aggregation could also be modulated post-liposome assembly by the addition of distinct small molecule beta-sheet breakers. Immunization of both mice and monkeys with a model liposomal vaccine containing beta-sheet aggregated lipopeptide (Palm1-15) induced polyclonal IgG antibodies that specifically recognized beta-sheet multimers over monomer or non-pathological native protein. The rational design of liposome-bound peptide immunogens with defined conformation opens up the possibility to generate vaccines against a range of protein misfolding diseases, such as Alzheimer disease.