Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments

Abstract

Glycoconjugates are major constituents of mammalian cells that are formed via covalent conjugation of carbohydrates to other biomolecules like proteins and lipids and often expressed on the cell surfaces. Among the three major classes of glycoconjugates, proteoglycans and glycoproteins contain glycans linked to the protein backbone via amino acid residues such as Asn for N-linked glycans and Ser/Thr for O-linked glycans. In glycolipids, glycans are linked to a lipid component such as glycerol, polyisoprenyl pyrophosphate, fatty acid ester, or sphingolipid. Recently, glycoconjugates have become better structurally defined and biosynthetically understood, especially those associated with human diseases, and are accessible to new drug, diagnostic, and therapeutic developments. This review describes the status and new advances in the biological study and therapeutic applications of natural and synthetic glycoconjugates, including proteoglycans, glycoproteins, and glycolipids. The scope, limitations, and novel methodologies in the synthesis and clinical development of glycoconjugates including vaccines, glyco-remodeled antibodies, glycan-based adjuvants, glycan-specific receptor-mediated drug delivery platforms, etc., and their future prospectus are discussed.

Catalytic Approaches to Chemo- and Site-Selective Transformation of Carbohydrates

“…Selective modification of glycoproteins is also an important yet unsettled transformation. Currently, glycoproteins are synthesized through sequential coupling (e.g., native chemical ligation) of peptide fragments possessing a preinstalled oligosaccharide motif. , If selective postfunctionalization, or “sugar-editing”, of glycoproteins in flasks or even on cell surfaces becomes possible, it would have a huge impact in glycobiology fields . Whereas genetic engineering can readily produce mutated proteins, chemistry is only feasible to mutate sugars.…”

Carriers and Antigens: New Developments in Glycoconjugate Vaccines

“…Soriaul et al, Shivatare et al and Hossain et al gave an excellent overview of the current field of carbohydrate-based cancer vaccines. This included potential carrier proteins, adjuvants, and modifications of TACA antigens to improve stability, reduce hydrolytic cleavage and the cost of large-scale chemical or enzymatical synthesis [ 128 , 129 , 130 ]. Another area where carbohydrate-based conjugate vaccines find their application is the field of neurodegenerative diseases such as Alzheimer’s disease [ 131 ].…”

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

“…In our previous study, the oligosaccharide moiety of GH or SSEA4 conjugated with DT and adjuvanted with C34, an analogue of the glycolipid α-GalCer designed to induce a class-switch and to enhance immune response with a balanced Th1/Th2 ratio, was demonstrated to successfully elicit immune responses against breast cancer in mice. , Interestingly, the GH-DT vaccine elicited antibody responses against the oligosaccharides of all three globo-series GSLs, while SSEA4-DT vaccine induced antibodies against SSEA4 glycan only and SSEA3-DT vaccine induced weak and non-selective immune responses . The same phenomenon was observed in human trials with GH-DT and GH-KLH vaccines . These results prompted us to speculate that the oligosaccharide-conjugate vaccine is probably more susceptible to glycosidase-mediated processing to generate SSEA3 oligosaccharide, the common epitope of all three globo-series GSLs, thereby eliciting antibody responses against all three globo-series GSLs.…”

“…23 The same phenomenon was observed in human trials with GH-DT and GH-KLH vaccines. 21 These results prompted us to speculate that the oligosaccharide-conjugate vaccine is probably more susceptible to glycosidase-mediated processing to generate SSEA3 oligosaccharide, the common epitope of all three globo-series GSLs, thereby eliciting antibody responses against all three globo-series GSLs. In this study, we tested the hypothesis in animal models and investigated the mechanism of antigen processing and presentation of the oligosaccharide moiety of GH-DT vaccine.…”