Total Synthesis and Immunological Evaluation of the Tri-d-glycero-d-manno-heptose Antigen of the Lipopolysaccharide as a Vaccine Candidate against Helicobacter pylori

Abstract

Helicobacter pylori, the most common cause of chronic gastritis, peptic ulcers, and gastric cancers, infects around half of the world’s population. Although the drawbacks of antibiotic-based combination therapy are emerging, no effective vaccine is available to prevent H. pylori infections. Here, we describe the total synthesis of the unique α-(1→3)-linked tri-d-glycero-d-manno-heptose antigen from the lipopolysaccharide of H. pylori serogroups O3 and O6 and strains MO19, D2, D4, and D5 based on de novo synthesis of the differentially protected d-glycero-d-manno-heptosyl building blocks. Immunization of mice with the semisynthetic glycoconjugate elicited a very robust T-cell-dependent antigen-specific immune response, resulting in very high titers of IgG1 and IgG2b protective antibody isotypes. The postimmune sera recognized H. pylori NCTC 11637 and bound strongly to the surface of the intact bacteria.

Immunological Exploration of Helicobacter pylori Serotype O2 O‐Antigen by Using a Synthetic Glycan Library

“…Prevention of H. pylori infections with an effective vaccine would be preferred over antibiotic treatments [ 9 ] as H. pylori vaccines have been explored. [ 10 ] An H. pylori O‐antigen serotyping system has designated H. pylori serotypes O1 to O6 since 1992. [ 11 ] Serotyping of H. pylori with monoclonal antibodies against Lewis antigens identified H. pylori serotype O2 as non‐typeable.…”

Application of Redox-Active Ester Catalysis to the Synthesis of Pyranose Alkyl C-Glycosides

“…Carbohydrates are diverse biomolecules that are implicated in multiple natural processes, such as protein folding, intracellular communication, and bacterial pathogenesis. , Much work in recent years has been devoted to the production of O-linked glycans as new therapeutics and glycobiological probes, − but the reactivity of O linkages to acid hydrolysis and enzymatic degradation can hinder the efficacy of these products in vivo . One way to address this issue is to replace the oxygen linkage with a methylene unit, which can increase the stability of therapeutic glycans without compromising their biological activity. − For example, alkyl exo - C -glycoside derivatives of KRN-7000, an immunostimulatory galactosyl ceramide derivative of sponge Agelas mauritianus glycolipid extracts (Figure ), were found to better activate natural killer T-cells against murine melanoma than O -glycoside derivatives at similar doses. , Alkyl C -glycosides have also been evaluated as competitive antagonists of DC-SIGN, a dendritic cell C-type lectin specific for l -fucose and d -mannose residues located in Le x antigen and high-mannose-containing viral glycoproteins, respectively .…”

“…This modification improved the resolution of the reducing sugar H2 and H3 signals, allowing for their assignment by COSY and HSQC experiments. Assuming an energetically favored 4 C 1 conformation, we could then target the H2 signal by NOEDIFF to confirm the D- mannose orientation of the C2,3 syn diol through the observed absence of the H2−H4 NOE effect, which would be expected for the alternate D-allose configuration (see the Supporting Information).…”

Promoter-Controlled Synthesis and Antigenic Evaluation of Mannuronic Acid Alginate Glycans of Pseudomonas aeruginosa

“…To screen out the optimal epitope of the synthetic mannuronic acid alginate glycan antigens, synthesis of six glycoconjugates was performed (Scheme ). By employing the bifunctional di­( N -succinimidyl) glutarate (DSG) as the linker, the six mannuronic acid alginate glycan antigens 21–26 were first reacted with the DSG linker to give the desired activated monoesters, which were then subjected to covalent coupling with human serum albumin (HSA) to produce glycoconjugates HSA- 21 –HSA- 26 , respectively (see the Supporting Information for details).…”