Chemical Synthesis of Truncated Capsular Oligosaccharide of Serotypes 6C and 6D of Streptococcus pneumoniae with Their Immunological Studies.

Serotypes 6C and 6D of Streptococcus pneumoniae are two major variants that cause invasive pneumococcal disease (IPD) in serogroup 6 alongside serotypes 6A and 6B. Since the introduction of the pneumococcal conjugate vaccines PCV7 and PCV13, the number of cases of IPD caused by pneumococcus in children and the elderly population has greatly decreased. However, with the widespread use of vaccines, a replacement effect has recently been observed among different serotypes and lowered the effectiveness of the vaccines. To investigate protection against the original serotypes and to explore protection against variants and replacement serotypes, we created a library of oligosaccharide fragments derived from the repeating units of the capsular polysaccharides of serotypes 6A, 6B, 6C, and 6D through chemical synthesis. The library includes nine pseudosaccharides with or without exposed terminal phosphate groups and four pseudotetrasaccharides bridged by phosphate groups. Six carbohydrate antigens related to 6C and 6D were prepared as glycoprotein vaccines for immunogenicity studies. Two 6A and two 6B glycoconjugate vaccines from previous studies were included in immunogenicity studies. We found that the conjugates containing four phosphate-bridged pseudotetrasaccharides were able to induce good immune antibodies and cross-immunogenicity by showing superior activity and broad cross-protective activity in OPKA bactericidal experiments.

Mechanism of Antigen Presentation and Specificity of Antibody Cross-Reactivity Elicited by an Oligosaccharide-Conjugate Cancer Vaccine.

Polysaccharides have been successfully used as immunogens for the development of vaccines against bacterial infection; however, there are no oligosaccharide-based vaccines available to date and no previous studies of their processing and presentation. We reported here the intracellular enzymatic processing and antigen presentation of an oligosaccharide-conjugate cancer vaccine prepared from the glycan of Globo-H (GH), a globo-series glycosphingolipid (GSL). This oligosaccharide-conjugate vaccine was shown to elicit antibodies against the glycan moieties of all three globo-series GSLs that are exclusively expressed on many types of cancer and their stem cells. To understand the specificity and origin of cross-reactivity of the antibodies elicited by the vaccine, we found that the vaccine is first processed by fucosidase 1 in the early endosome of dendritic cells to generate a common glycan antigen of the GSLs along with GH for MHC class II presentation. This work represents the first study of oligosaccharide processing and presentation and is expected to facilitate the design and development of glycoconjugate vaccines based on oligosaccharide antigens.

Synthetic Library of Oligosaccharides Derived from the Capsular Polysaccharide of Streptococcus pneumoniae Serotypes 6A and 6B and Their Immunological Studies.

Streptococcus pneumoniae serotypes 6A and 6B are two of the common causes of invasive pneumococcal diseases. Although capsular polysaccharide conjugates of these two serotypes are included in the leading 13-valent pneumococcal conjugate vaccine, its low immunogenicity and high threshold for manufacturing technology indicated the need for vaccine improvement. Structurally defined synthetic immunogens have potential in dealing with these problems. To this end, we built a library of capsular polysaccharide fragments through convergent chemical synthesis in [2 + 2], [4 + 4], [4 + 3], [4 + 2], and [4 + 1] coupling manners. The library is comprised of 18 glycan antigens from trisaccharides to pseudo-octasaccharides, derived from the capsular repeating phosphorylated pseudo-tetrasaccharide with or without phosphate. Eight of them were selected for mouse immunization and further immunological studies. Four pseudo-tetrasaccharides with terminal or bridging phosphate elicited opsonic antibodies, which exhibited bactericidal activities and moderate cross-reactivities.

Total Synthesis of (+)-Lycoricidine and Conduramine B-1, ent-C-1, C-4, D-1, ent-F-1, and ent-F-4, and Formal Synthesis of (-)-Laminitol: a C2-Symmetric Chiral-Pool-Based Flexible Strategy.

A facile and diversity-oriented synthetic strategy toward aminocyclitol natural products from inexpensive C2-symmetric l-tartaric acid was developed. The pivotal epoxide was used as a common intermediate to accomplish eight diverse target molecules in six to eleven steps. Various allyl-amine-type conduramines were synthesized in a diastereoselective manner. Heck arylation was explored to construct a phenanthridone ring in a concise synthesis of (+)-lycoricidine. In addition, a highly efficient formal synthesis of (-)-laminitol was developed.

Synthesis and Bioassay of Neurogenically Potent Gangliosides DSG-A, Hp-s1 and Their Analogues.

In the search of a potent candidate for neurotherapy, we designed and synthesized various analogues of ganglioside Hp-s1. The modification includes the change in hydrophobicity by varying the carbon chain length, altering the number of hydrogen bonds, and replacing the anomeric atom. The chemical synthesis was carried out by using various methods and discussed in details. The neuritogenic activities of these analogues are confirmed in a human neuroblastoma cell line SH-SY5Y. A higher activity of ganglioside Hp-s1 analogue on IL-17A transcript upregulation than ganglioside Hp-s1 was found.