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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >A Modular Approach to Assembly of Totally Synthetic Self-adjuvanting Lipopeptide-based Vaccines Allows Conformational Epitope Building
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A Modular Approach to Assembly of Totally Synthetic Self-adjuvanting Lipopeptide-based Vaccines Allows Conformational Epitope Building

机译：基于组装的基于脂肽的全合成自佐剂的模块化方法允许构象表位的建立。

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The technology described here allows the chemical synthesis of vaccines requiring correctly folded epitopes and that contain difficult or long peptide sequences. The final self-adjuvanting product promotes strong humoral and/or cell-mediated immunity. A module containing common components of the vaccine (T helper cell epitope and the adjuvanting lipid moiety S-[2,3-bis(palmitoyloxy)propyl]cysteine) was assembled to enable a plug and play approach to vaccine assembly. The inclusion within the module of a chemical group with chemical properties complementary and orthogonal to a chemical group present in the target epitope allowed chemoselective ligation of the two vaccine components. The heat-stable enterotoxin of enterotoxigenic Escherichia coli that requires strict conformational integrity for biological activity and the reproductive hormone luteinizing hormone-releasing hormone were used as the target epitopes for the antibody vaccines. An epitope from the acid polymerase of influenza virus was used to assemble a CD8+ T cell vaccine. Evaluation of each vaccine candidate in animals demonstrated the feasibility of the approach and that the type of immune response required, viz. antibody or cytotoxic T lymphocyte, dictates the nature of the chemical linkage between the module and target epitope. The use of a thioether bond between the module and target epitope had little or no adverse effect on antibody responses, whereas the use of a disulfide bond between the module and target epitope almost completely abrogated the antibody response. In contrast, better cytotoxic T lymphocyte responses were obtained when a disulfide bond was used.
机译：此处描述的技术允许化学合成需要正确折叠的表位且含有困难或较长肽序列的疫苗。最终的自我佐剂产品可增强体液和/或细胞介导的免疫力。组装了包含疫苗常见成分（T辅助细胞表位和佐剂脂质部分S- [2,3-双（棕榈酰氧基）丙基]半胱氨酸的模块），以实现即插即用的疫苗组装方法。在模块内包含具有与靶表位中存在的化学基团互补并正交的化学性质的化学基团允许两种疫苗组分的化学选择性连接。要求严格构象完整性以实现生物学活性的产肠毒素大肠杆菌的热稳定肠毒素和生殖激素黄体生成素释放激素被用作抗体疫苗的目标表位。用流感病毒酸性聚合酶的抗原决定簇组装CD8 + T细胞疫苗。对动物中每种候选疫苗的评估证明了该方法的可行性以及所需的免疫应答类型，即。抗体或细胞毒性T淋巴细胞决定了模块与目标表位之间化学键的性质。在模块和靶标表位之间使用硫醚键对抗体应答几乎没有或没有不利影响，而在模块和靶标表位之间使用二硫键几乎完全消除了抗体应答。相反，当使用二硫键时，可获得更好的细胞毒性T淋巴细胞反应。

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