School of Chemistry and Molecular Biosciences (SCMB), The University of Queensland, QLD 4072, Queensland, Australia.
J Med Chem. 2010 Nov 25;53(22):8041-6. doi: 10.1021/jm1007787. Epub 2010 Oct 28.
Immunological assessment of group A streptococcal (GAS) branched lipopeptides demonstrated the impact of spatial arrangement of vaccine components on both the quality and quantity of their immune responses. Each lipopeptide was composed of three components: a GAS B-cell epitope (J14), a universal CD4(+) T-cell helper epitope (P25), and an immunostimulant lipid moiety that differs only in its spatial arrangement. The best systemic immune responses were demonstrated by a lipopeptide featuring the lipid moiety at the lipopeptide C-terminus. However, this candidate did not achieve protection against bacterial challenge. The best protection (100%) was shown by a lipopeptide featuring a C-terminal J14, conjugated through a lysine residue to P25 at the N-terminus, and a lipid moiety on the lysine side chain. The former candidate features α-helical conformation required to produce protective J14-specific antibodies. Our results highlight the importance of epitope orientation and lipid position in the design of three-component synthetic vaccines.
免疫评估表明 A 组链球菌（GAS）分支脂肽的空间排列方式对其免疫反应的质量和数量都有影响。每个脂肽由三个成分组成：GAS B 细胞表位（J14）、通用 CD4+T 细胞辅助表位（P25）和免疫刺激脂质部分，它们仅在空间排列上有所不同。具有脂肽 C 末端脂质部分的脂肽表现出最佳的全身免疫反应。然而，该候选物不能提供针对细菌挑战的保护。具有 C 末端 J14 的脂肽表现出最佳的保护（100%），该脂肽通过赖氨酸与 N 末端的 P25 连接，赖氨酸侧链上带有脂质部分。前一种候选物具有产生保护性 J14 特异性抗体所需的α-螺旋构象。我们的研究结果强调了三组分合成疫苗中表位取向和脂质位置的重要性。
