Chemical Synthesis and Immunological Evaluation of Helicobacter pylori Serotype O6 Tridecasaccharide O‐Antigen Containing a dd‐Heptoglycan

Abstract

The development of glycoconjugate vaccines against Helicobacter pylori is challenging. An exact epitope of the H. pylori lipo‐polysaccharide (LPS) O‐antigens that contain Lewis determinant oligosaccharides and unique dd‐heptoglycans has not yet been identified. Reported here is the first total synthesis of H. pylori serotype O6 tridecasaccharide O‐antigen containing a terminal Ley tetrasaccharide, a unique α‐(1→3)‐, α‐(1→6)‐, and α‐(1→2)‐linked heptoglycan, and a β‐d‐galactose connector, by an [(2×1)+(3+8)] assembly sequence. Seven oligosaccharides covering different portions of the entire O‐antigen were prepared for immunological investigations with a particular focus on elucidation of the roles of the dd‐heptoglycan and Ley tetrasaccharide. Glycan microarray analysis of sera from rabbits immunized with isolated serotype O6 LPS revealed a humoral immune response to the α‐(1→3)‐linked heptoglycan, a key motif for designing glycoconjugate vaccines for H. pylori serotype O6.

Total synthesis of the O-antigen repeating unit of Providencia stuartii O49 serotype through linear and one-pot assemblies

“…Due to their importance in regulating the host's immune system, the bacterial cell surface LPS in general and the O-antigens in particular have been proposed and reported as candidates for vaccine development [1][2][3][4][5][6][7][8]. This objective has been proposed to be achieved by the synthesis of chemically homogeneous glycoconjugates bearing the O-antigen oligosaccharide conjugated to peptides for eliciting the desired immune response through vaccines [9][10][11][12][13][14][15][16][17][18][19][20][21]. For the above purposes, large scale access to pure, defined, and homogeneous samples of the desired LPS oligosaccharides are essential for realization of the goal towards vaccine development against these pathogens .…”

Cascade In Situ Phosphorylation and One-Pot Glycosylation for Rapid Synthesis of Heptose-Containing Oligosaccharides

“…Such lengthy processes constitute a barrier for development of new glycosylation methods. As a consequence, the bacterial inner core oligosaccharides are still prepared by the less effective stepwise glycosylation. ,− …”

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

“…To develop carbohydrate-based vaccines against H. pylori infections, cell surface lipopolysaccharides (LPS) from H. pylori have been isolated and conjugated to carrier proteins for the evaluation of the resultant glycoconjugates as potential vaccine candidates. − Remarkably, the delipidated LPS-based conjugates induced a strong and specific immune response in mice and rabbits, and the postimmune sera displayed broad cross-reactivity against both homologous and heterologous strains from the clinical isolates of H. pylori . − To elucidate the structure–activity relationship and the minimal epitope of H. pylori LPS, chemical synthesis of the partial structures of the LPS is highly desirable . As an unusual and conserved homopolymer that is located at the intervening region between the outer O chain and the core structure, understanding the immunological function of the d - glycero- d - manno -heptan of the LPS of H. pylori such as serogroups O3 and O6 and strains MO19, D2, D4, and D5 is very attractive .…”

“…Compared with the traditional preparation of d - glycero - d - manno -heptose building blocks using the homologation strategy that often employed highly toxic osmium salt for dihydroxylation of the double bond, , de novo synthesis represents an appealing alternative strategy for producing rare heptose building blocks. , Here, we report the total synthesis of the α-(1→3)-linked tri- d - glycero - d - manno -heptose antigen based on de novo synthesis of the differentially protected d - glycero - d - manno -heptosyl building blocks. Immunization of mice with the resulting semisynthetic glycoconjugate generates IgG antibodies that bound strongly to the intact H. pylori bacteria, indicating that the α-(1→3)-linked tri- d - glycero - d - manno -heptose is a highly promising antigen for vaccine development against H. pylori infections.…”