Synthetic virus-like particles from self-assembling coiled-coil lipopeptides and their use in antigen display to the immune system
Synthetic virus-like particles from self-assembling coiled-coil lipopeptides and their use in antigen display to the immune system
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DOI：
10.1002/anie.200702805
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Robinson, John A.
中科院分区：
文献类型：
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作者：
Boato, Francesca;Thomas, Richard M.;Robinson, John A.
病毒样颗粒(VLP)在制药和生物技术研究中引起了极大的兴趣。[1]VLP通常由重组蛋白组成，例如，乙肝病毒的衣壳，[2]有时与核酸结合，如噬菌体，[3]，它们可能包含病毒外壳蛋白，如病毒小体。[4]许多天然VLP的自然自组装核心结构可以被利用来在颗粒的表面显示一个抗原的多个副本，例如，通过将编码肽环的寡核苷酸插入适当的结构基因中，或者通过将半抗原与重组VLP化学结合。在病毒或细菌表面显示重复的抗原结构以产生强大的免疫反应的重要性现在已经得到证实。[5，6]VLP还可能包含天然的T辅助细胞表位和病原体相关的分子模式，这些表位和病原体相关的分子模式被先天性免疫系统识别，从而进一步增强免疫反应。然而，所有前面描述的VLP都需要使用细胞培养或重组DNA方法来生产和/或工程。我们探索了使用人工合成的构建块来生产VLP的可能性，这种构建块可以自组装成大小和组成与自然病毒相似的颗粒，在这种情况下，含有蛋白质和脂肪，但不含核酸。这种人工合成的病毒样颗粒(SVLP)可能会保留自然来源的VLP作为抗原递送载体的优点，但除此之外，还可以使用各种合成化学方法进行优化和生产。基本构件由含有卷曲螺旋序列的脂肽组成。卷曲螺旋基序驱动多肽链的自组装成平行的螺旋束。此外，脂类成分，通常是具有两个长脂肪链的磷脂，在每个肽链的N端偶联。在盘绕的线圈自结合成平行螺旋束之后，得到的脂链簇驱动多个盘绕的线圈的自组装
Virus-like particles (VLPs) have attracted great interest in pharmaceutical and biotechnological research.[1] VLPs are typically composed of recombinant proteins, for example, the capsid of the hepatitis B virus,[2] sometimes in combination with nucleic acids, such as bacteriophage,[3] or they may contain a viral envelope in addition to viral coat proteins, such as virosomes.[4] The natural self-assembling core structures of many natural VLPs can be exploited to display multiple copies of an antigen across the surface of the particle, for example, by inserting oligonucleotides encoding peptide loops into the appropriate structural genes, or by chemically conjugating haptens to recombinant VLPs. The importance of displaying repeated antigenic structures across a viral or bacterial surface to generate robust immune responses is now well established.[5, 6] VLPs may also contain natural T-helpercell epitopes and pathogen-associated molecular patterns that are recognized by the innate immune system, which further enhance immune responses. All the previously described VLPs, however, require the use of cell-culture or recombinant-DNA methods for production and/or engineering. We have explored the possibility of producing VLPs using artificial synthetically derived building blocks, which can self-assemble into particles having a size and composition similar to that of natural viruses, in this case containing protein and lipid, but not nucleic acids. Such synthetic viruslike particles (SVLPs) might then retain the advantages of naturally derived VLPs as antigen delivery vehicles, but in addition could be optimized and produced using a myriad of synthetic chemical methods.The SVLPs described herein harness the principles of protein–protein as well as lipid–lipid recognition to drive selfassembly. The basic building block comprises a lipopeptide containing a coiled-coil sequence.[7] The coiled-coil motif drives self-assembly of the peptide chains into parallel helical bundles. In addition, a lipid component, typically a phospholipid having two long fatty acid chains, is coupled at the N terminus of each peptide chain. After self-association of the coiled coil into a parallel helical bundle, the resulting cluster of lipid chains drives self assembly of multiple coiled-coil