A Fluorinated Sialic Acid Vaccine Lead Against Meningitis B and C

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.

Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine

“…To mitigate hydrolytic cleavage of the lipid mimetic, fluorination at C2 of the glucose unit, which is not directly involved in the interaction with CTB 5 but carries the lipid anchor, was envisaged . Since site-selective deoxyfluorination of commercial GM1 is not synthetically feasible, success would be conditional on the development of a stereocontrolled, de novo synthesis of the fluorinated pentasaccharide. , Strategically leveraging fluorine-directed glycosylation is appealing to introduce the key galactose (β1 → 3) and glucose units in a stereocontrolled manner.…”