PDF(Pubmed)
Abstract：
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 Neisseria meningitidis 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 in vitro 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.
摘要：
受细菌荚膜多糖（CPS）中α-（2,9）-唾液酸表位特异性的启发，一种双重氟化的二糖已被验证为针对脑膜炎奈瑟菌血清群C和/或B的疫苗先导。模拟氟在药物发现中的重要性，这种分子编辑方法有多种用途，范围从控制α选择性化学唾液酸化到减轻竞争性消除。二唾液酸苷与两种载体蛋白（CRM197和PorA）的缀合可以产生半合成疫苗；然后在六组六只小鼠中进行了研究。比较所形成的抗体的个体水平并分类为高度聚糖特异性和保护性。所有糖缀合物均诱导稳定且长期的IgG应答并实现与天然CPS表位的结合。产生的抗体对MenC和/或MenB具有保护性;这在体外通过SBA和OPKA测定进行了验证。通过将MenC的氟化聚糖表位与MenB的外细胞膜蛋白合并，产生了针对两种血清群的二价疫苗.据设想，这种合成的验证，氟化二唾液酸苷生物等排体作为一种有效的抗原将开辟新的治疗途径。
