The translation of biological glycosylation in humans to the clinical applications involves systematic studies using homogeneous samples of oligosaccharides and glycoconjugates, which could be ...accessed by chemical, enzymatic or other biological methods. However, the structural complexity and wide-range variations of glycans and their conjugates represent a major challenge in the synthesis of this class of biomolecules. To help navigate within many methods of oligosaccharide synthesis, this Perspective offers a critical assessment of the most promising synthetic strategies with an eye on the therapeutically relevant targets.
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Glycoscience research has been significantly impeded by the complex compositions of the glycans present in biological molecules and the lack of convenient tools suitable for studying the ...glycosylation process and its function. Polysaccharides and glycoconjugates are not encoded directly by genes; instead, their biosynthesis relies on the differential expression of carbohydrate enzymes, resulting in heterogeneous mixtures of glycoforms, each with a distinct physiological activity. Access to well-defined structures is required for functional study, and this has been provided by chemical and enzymatic synthesis and by the engineering of glycosylation pathways. This review covers general methods for preparing glycans commonly found in mammalian systems and applying them to the synthesis of therapeutically significant glycoconjugates (glycosaminoglycans, glycoproteins, glycolipids, glycosylphosphatidylinositol-anchored proteins) and the development of carbohydrate-based vaccines.
Heparin (H) and heparan sulfate (HS) belong to the glycosaminoglycan (GAG) family of oligosaccharides, and their sequences and sulfation patterns are known to regulate the functions of various ...proteins in biological processes. Among these, the 6-
-sulfation of HS/H contributes most significantly to the structural diversity and binding interactions. However, the synthesis of HS with defined sulfation patterns remains a major challenge. Herein, we report a highly efficient and programmable one-pot method for the synthesis of protected heparin pentasaccharides using thioglycoside building blocks with optimized relative reactivities to allow the selective deprotection and preparation of regiodefined sulfate derivatives.
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Carbohydrates have been shown to play important roles in biological processes. The pace of development in carbohydrate research is, however, relatively slow due to the problems associated with the ...complexity of carbohydrate structures and the lack of general synthetic methods and tools available for the study of this class of biomolecules. Recent advances in synthesis have demonstrated that many of these problems can be circumvented. In this Review, we describe the methods developed to tackle the problems of carbohydrate‐mediated biological processes, with particular focus on the issue related to the development of the automated synthesis of oligosaccharides. Further applications of carbohydrate microarrays and vaccines to human diseases are also highlighted.
Sweet dreams: Carbohydrates play important roles in biological processes. The pace of carbohydrate research is, however, relatively slow due, amongst other things, to the lack of general synthetic methods. Current developments in the automated synthesis of oligosaccharides can help overcome many of these problems and to pave the way for biomedical applications.
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Idraparinux is a fully O-sulfated α-methyl glycoside of heparin pentasaccharide motif known to interact with the antithrombin III domain and act as anticoagulant. The current most effective synthesis ...of Idraparinux is complicated and nonstereoselective, requiring numerous stepwise procedures with low yields. We report here an efficient modular one-pot synthesis of Idraparinux involving the use of a glycosyl phosphate with 6-O-tert-butyl diphenyl silyl group and a d-glucuronic acid-containing disaccharide thioglycoside with 6-O-acetyl group as donor building blocks for the α-directing one-pot glycosylations with an l-iduronic acid-containing disaccharide acceptor building block. The uronic acid was incorporated in a disaccharide module used in the one-pot synthesis to avoid the complicated late-stage installation of these acidic sugars. The one-pot synthesis of Idraparinux demonstrated here is an effective strategy and should be applicable to the modular assembly of other heparan sulfates with regiodefined sulfation pattern for functional study.
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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.
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The clinically approved Fondaparinux (Arixtra) has been used for the treatment of deep vein thrombosis (DVT) and acute pulmonary embolism (PE) since 2002, and considered to be better than the low ...molecular-weight heparin (LMWH) in terms of anticoagulation response, duration of action and biosafety. However, the synthetic methods developed for its manufacture in the past years are relatively complicated thus restricting its extensive use. We reported here a potentially scalable and programmable one-pot synthesis of Fondaparinux using the 1,2,2 strategy and designed thioglycosides with well-defined reactivity as building blocks.
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The stereoselectivity and yield in glycosylation reactions are paramount but unpredictable. We have developed a database of acceptor nucleophilic constants (Aka) to quantify the nucleophilicity of ...hydroxyl groups in glycosylation influenced by the steric, electronic and structural effects, providing a connection between experiments and computer algorithms. The subtle reactivity differences among the hydroxyl groups on various carbohydrate molecules can be defined by Aka, which is easily accessible by a simple and convenient automation system to assure high reproducibility and accuracy. A diverse range of glycosylation donors and acceptors with well‐defined reactivity and promoters were organized and processed by the designed software program “GlycoComputer” for prediction of glycosylation reactions without involving sophisticated computational processing. The importance of Aka was further verified by random forest algorithm, and the applicability was tested by the synthesis of a Lewis A skeleton to show that the stereoselectivity and yield can be accurately estimated.
A so‐called “GlycoComputer” program has been developed to foresee and predict the yield and stereoselectivity of glycosylation reactions based on the properties of various donors, acceptors, activation systems and solvents. The program statistically analyzes and compares the relative reactivity value (RRV) of donors and the acceptor nucleophilic constant (Aka) of acceptors.
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The incidence and mortality rate of oral cancer continue to rise, partly due to the lack of effective early diagnosis and increasing environmental exposure to cancer-causing agents. To identify new ...markers for oral cancer, we used a sialylation probe to investigate the glycoproteins differentially expressed on oral cancer cells. Of the glycoproteins identified, B7 Homolog 3 (B7-H3) was significantly overexpressed in oral squamous cell carcinoma (OSCC), and its overexpression correlated with larger tumor size, advanced clinical stage, and low survival rate in OSCC patients. In addition, knockdown of B7-H3 suppressed tumor cell proliferation, and restoration of B7-H3 expression enhanced tumor growth. It was also found that the N-glycans of B7-H3 from Ca9-22 oral cancer cells contain the terminal α-galactose and are more diverse with higher fucosylation and better interaction with DC-SIGN DC-specific intercellular adhesion molecule-3 (ICAM-3)–grabbing nonintegrin and Langerin on immune cells than that from normal cells, suggesting that the glycans on B7-H3 may also play an important role in the disease.
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