Chemical Synthesis of the Highly Sterically Hindered Core Undecasaccharide of Helicobacter pylori Lipopolysaccharide for Antigenicity Evaluation with Human Serum

Abstract

Helicobacter pylori, listed as a human carcinogen by the Department of Health and Human Services, colonizes the gastric mucosa of more than half of the world's population. The individuals infected with H. pylori have a high risk to develop chronic gastritis, peptic ulcers, and even gastric cancer. The conserved core structure of H. pylori lipopolysaccharide (LPS) has been regarded as a promising candidate structure for development of a glycoconjugate vaccine targeting multiple serotypes. Here, we report a total synthesis of the core undecasaccharide of H. pylori LPS and its subunit antigens. The match and mismatch between the glycosyl donor and acceptor caused by the inert hydroxyl groups were addressed by a judicious choice of orthogonal protection strategies and glycosylation conditions. A combination of acyl remote participation and solvent effects has been applied for selective formation of the five 1,2-cis-glucosidic bonds. The high steric hindrance induced by the high carbon sugars and trinacriform architecture required that the core undecasaccharide was synthesized through a finely tuned linear assembly [2 + (1 + (3 + (1 + (1 + 3))))] rather than convergent strategies. An antigenicity evaluation using glycan microarrays showed that an α-(1 → 6)-glucan trisaccharide is recognized by IgG antibodies in sera of H. pylori-infected patients. The phosphate group of the inner core trisaccharide key epitope is very important for IgG recognition. These findings are an important step toward designing carbohydrate-based vaccines against H. pylori.

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

“…[ 25 ] Glycan microarrays are an efficient means to investigate the antigenicity of oligosaccharides with different lengths and frameshifts. [ 5,26 ] The synthetic oligosaccharides and O2 LPS were printed on glycan microarrays for antigenicity evaluation with O2 LPS immunized positive rabbit sera (anti‐O2 LPS antisera) (Figure 2A). [ 20 ] The extracted O1 and O6 LPS were used as controls.…”

“…[ 20 ] The extracted O1 and O6 LPS were used as controls. [ 5 ] Almost all oligosaccharide fragments were recognized by IgG antibodies in anti‐O2 LPS antisera (Figures 2B and 2C). Both trisaccharides HPO2G‐3b and HPO2G‐3a showed stronger binding affinity to anti‐O2 LPS IgG antibodies among the fragments with different nonreducing ends.…”

“…[ 3 ] The bacterium is considered a group I carcinogen by the World Health Organization (WHO) [ 4 ] and listed as a human carcinogen by the U.S. Department of Health and Human Services (HHS). [ 5 ] H. pylori infection was considered as the most pathogenic factor for infection‐related cancers in 2018. [ 6 ] H. pylori infections are treated primarily with antibiotics, but growing antibiotic resistance of H. pylori is a serious concern, [ 7 ] while antibiotics fail to protect adults against re‐infection.…”

Modular Synthesis of a Tridecasaccharide Motif of Bacteroides vulgatus Lipopolysaccharides against Inflammatory Bowel Diseases through an Orthogonal One‐Pot Glycosylation Strategy

“…Owing to regio-and stereochemical problems, traditional glycan synthesis usually involves time-consuming and tedious processes. [13] Although significant progress has been made in carbohydrate synthesis for the exploitation of new carbohydrate-based drugs and understanding their functions in recent decades, [14,15] efficient access to long, branched and complex carbohydrates with many 1,2-cis glycosidic linkages remains a formidable challenge. [16][17][18][19][20] Herein, we report the first and modular chemical synthesis of the homogeneous and well-defined tridecasaccharide motif 1 from BVMPK LPS with a core oligosaccharide and three O-chain disaccharide repeating units through one-pot glycan assembly based on glycosyl ortho-(1phenylvinyl)benzoates [21] (PVBs), which not only accelerated the syntheis, [22] but also solved the issues inherent to one-pot synthesis on the basis of thioglycosides (Figure 1B).…”

Chemoenzymatic Total Synthesis of Haemophilus ducreyi Lipooligosaccharide Core Octasaccharides Containing Natural and Unnatural Sialic Acids

“…The preparation of H. ducreyi LOS core octasaccharides containing natural and unnatural sialic acids started with chemical synthesis of hexasaccharide 1 , followed by enzymatic extension to produce the target glycans 2 – 6 (Scheme ). The chemical synthesis of 1 remains challenging due to the requirement of the efficient preparation of multiple higher-carbon sugar building blocks such as l , d -Hep, d , d -Hep, and Kdo, as well as the stereoselective construction of glycosidic bonds. − It was assumed that protected hexasaccharide would be synthesized through a convergent and stereocontrolled [3 + 3] method from appropriately protected monosaccharide building blocks 7 – 12 . The ability to selectively remove orthogonal protecting groups 2-naphthylmethyl (Nap) , and levulinoyl (Lev) , as the corresponding acceptors makes it possible to glycosylate the C4 position of the l , d -Hep residue and the C6 position of the glucose (Glc) residue, respectively.…”