School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, 4072, Australia.
Institute for Molecular Biosciences, The University of Queensland, St. Lucia, QLD, 4072, Australia; Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Eur J Med Chem. 2019 Oct 1;179:100-108. doi: 10.1016/j.ejmech.2019.06.047. Epub 2019 Jun 18.
Synthetic peptide vaccines based on epitopes derived from the conserved region of M-protein are proving to be a realistic option for protection against group A streptococcus (GAS). However, peptide epitopes alone are poorly immunogenic due to lack of pathogen-associated structural patterns. Therefore, we developed a GAS peptide vaccine based on combined lipidic TLR 2 agonist and self-adjuvanting polymers. We synthesized three α-poly-l-glutamic acid (PGA) conjugated lipopeptides composed of 2-amino-d,l-hexadecanoic acid, GAS B-cell peptide epitope J8 (QAEDKVKQSREAKKQVEKALKQLEDKVQ) and universal T-helper epitope PADRE (AKFVAAWTLKAAA) in different spatial arrangements. The anionic lipopeptide conjugates formed nanoparticles via ionic-complexation with a cationic polymer, trimethyl chitosan (TMC). We demonstrated that the spatial arrangement of vaccine components has a significant influence on peptide conformation and particle formation and, as such, contributes to the differential efficacy and opsonin-mediated killing potential of nanovaccines. Nanoparticles carrying branched helical lipopeptide with T-helper epitope on free N-termini (NP3) stimulated the most potent humoral immune responses. Lipopeptides without TMC (LP1-LP3) and TMC nanoparticles of peptide alone (without lipid) NP (P1) were poor inducers of antibody production, indicating that both TMC and lipid are required to induce a strong opsonic immune response.
基于 M 蛋白保守区域表位的合成肽疫苗被证明是预防 A 组链球菌（GAS）的一种切实可行的选择。然而，由于缺乏病原体相关的结构模式，单独的肽表位免疫原性较差。因此，我们开发了一种基于脂质 TLR2 激动剂和自佐剂聚合物的 GAS 肽疫苗。我们合成了三种由 2-氨基-d,l-十六烷酸、GAS B 细胞肽表位 J8（QAEDKVKQSREAKKQVEKALKQLEDKVQ）和通用 T 辅助表位 PADRE（AKFVAAWTLKAAA）组成的 α-聚谷氨酸（PGA）缀合脂肽，其空间排列不同。带负电荷的脂肽缀合物通过与阳离子聚合物三甲基壳聚糖（TMC）的离子络合形成纳米颗粒。我们证明了疫苗成分的空间排列对肽构象和颗粒形成有显著影响，因此有助于纳米疫苗的功效和调理素介导的杀伤潜力的差异。带有游离 N 末端 T 辅助表位的支化螺旋脂肽的纳米颗粒（NP3）刺激产生最有效的体液免疫反应。没有 TMC 的脂肽（LP1-LP3）和没有脂质的肽的 TMC 纳米颗粒（NP（P1））诱导抗体产生的能力较差，表明 TMC 和脂质均是诱导调理素免疫反应所必需的。
