Institute for Organic Chemistry, University of Münster, Corrensstraße 36, Münster 48149, Germany.
Department of Biomolecular Systems, Max Planck Institute for Colloids and Interfaces, Am Mühlenberg 1, Potsdam 14476, Germany.
J Am Chem Soc. 2024 Jun 5;146(22):15366-15375. doi: 10.1021/jacs.4c03179. Epub 2024 May 20.
Inspired by the specificity of α-(2,9)-sialyl epitopes in bacterial capsular polysaccharides (CPS), a doubly fluorinated disaccharide has been validated as a vaccine lead against serogroups C and/or B. Emulating the importance of fluorine in drug discovery, this molecular editing approach serves a multitude of purposes, which range from controlling α-selective chemical sialylation to mitigating competing elimination. Conjugation of the disialoside with two carrier proteins (CRM197 and PorA) enabled a semisynthetic vaccine to be generated; this was then investigated in six groups of six mice. The individual levels of antibodies formed were compared and classified as highly glycan-specific and protective. All glycoconjugates induced a stable and long-term IgG response and binding to the native CPS epitope was achieved. The generated antibodies were protective against MenC and/or MenB; this was validated by SBA and OPKA assays. By merging the fluorinated glycan epitope of MenC with an outer cell membrane protein of MenB, a bivalent vaccine against both serogroups was created. It is envisaged that validation of this synthetic, fluorinated disialoside bioisostere as a potent antigen will open new therapeutic avenues.
受细菌荚膜多糖 (CPS) 中 α-(2,9)-唾液酸表位的特异性启发，一种双氟化二糖已被验证为针对血清群 C 和/或 B 的疫苗先导物。这种分子编辑方法模拟了氟在药物发现中的重要性，具有多种用途，包括控制 α-选择性化学唾液酸化和减轻竞争消除。将二唾液酸与两种载体蛋白（CRM197 和 PorA）缀合，生成半合成疫苗；然后在六组 6 只小鼠中进行了研究。比较了形成的抗体的个体水平，并将其分类为高度糖特异性和保护性。所有糖缀合物均诱导稳定且长期的 IgG 反应，并与天然 CPS 表位结合。所产生的抗体对 MenC 和/或 MenB 具有保护作用；这通过 SBA 和 OPKA 测定得到了验证。通过将 MenC 的氟化聚糖表位与 MenB 的外细胞膜蛋白融合，创建了针对这两个血清群的双价疫苗。预计将这种合成的、氟化的二唾液酸生物等排物作为有效的抗原进行验证将开辟新的治疗途径。
