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Glycomics: a pathway to a class of new and improved therapeutics

Key Points

  • Complex glycans are important modulators of numerous biological processes, ranging from organ development to wound healing to the modification of diseases such as cancer. Although there are some exceptions, glycans do not generally control biological processes in a digital 'on or off' manner; rather, they 'fine-tune' biological functions.

  • Complex glycans are either linear or branched structures that can exist alone or attached to other biomolecules. Owing to variation in branching patterns and in the individual monosaccharides that comprise the chain, glycans are information-dense biomolecules.

  • Recent advances in several areas of research — including the development of analytical techniques, numerous genetic studies, new synthetic strategies and the advent of bioinformatics platforms — have raised the exciting possibility that glycan-based drugs could be developed for many diseases.

  • Structure–function studies in this area have already led to important advances, both scientifically and in terms of drug development. Two examples of the latter are the development of second-generation antithrombotics with increased efficacy and increased clinical usefulness, and the development of improved forms of glycoprotein drugs.

  • The US National Institutes of Health has recently sponsored the development of a consortium that brings together leaders in the field of glycan chemistry and biology to systematically catalogue and study glycan structure and function. This endeavour promises to provide a wealth of important information for the development of novel therapeutics and diagnostics, in a similar way to other federally sponsored initiatives in genomics and proteomics.

Abstract

Complex glycans that are located at the surface of cells, deposited in the extracellular matrix and attached to soluble signalling molecules have a crucial role in the phenotypic expression of cellular genotypes. However, owing to their structural complexity and some redundancy in terms of structures that elicit a function, the therapeutic potential of complex glycans has not been well exploited, with a few notable exceptions. This review outlines recent advances that promise to increase our ability to use complex glycans as therapeutics. Opportunities for the development of further structure–function relationships for these complex molecules are also discussed.

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Figure 1: Biological roles of branched and linear glycans.
Figure 2: Structural complexity and information content of glycans.
Figure 3: New second-generation therapeutics based on glycan structures.
Figure 4: The Consortium for Functional Glycomics.

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Acknowledgements

We would like to thank G. Venkataraman for help with the manuscript. Financial support for this work was provided by the National Institutes of Health and a Glue Grant for the Consortium for Functional Glycomics.

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Correspondence to Ram Sasisekharan.

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R.S. is a consultant with Momenta Pharmaceuticals.

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DATABASES

Entrez Gene

ATIII

MGAT1

MGAT2

Online Mendelian Inheritance in Man

Alzheimer's disease

mucopolysaccharidosis type I

FURTHER INFORMATION

Consortium for Functional Glycomics (CFG)

Essentials of Glycobiology

Galectin 3 (human)

GenBank

Meetings Related to Glycosciences and Carbohydrates

Updates on the Consortium

Glossary

GLYCANS

Endogenous biomolecules that consist of monosaccharides that are O-linked to one another. Glycans can either be branched, in which several glycosidic linkages extend from a single monosaccharide, or linear, in which monosaccharides are linked to one another end-to-end.

SIALYATED

Sialic acid is an important 'capping' monosaccharide that imparts essential structural and biological information. For recombinant proteins, the presence of sialic-acid capping is important in the half-life and stability of the protein. Sialic-acid capping also has a role in a range of biological processes, including immune-system functioning.

HEPARIN

A linear polysaccharide consisting of a disaccharide repeat unit, in which each individual unit can be differentially sulphated, which leads to structural complexity. Heparin is used as an anticoagulant.

ANTITHROMBIN III

(ATIII). A serine protease inhibitor that interrupts the coagulation cascade to provide an important feedback loop. Heparin binds to ATIII, which causes a conformational change in the protein and promotes its anticoagulant function.

BIOINFORMATICS

Data integration, mining and comparison tools that are used to combine data sets.

ERYTHROPOIETIN

An endogenous glycoprotein, the main function of which is to stimulate the proliferation and differentiation of erythroid precursors in the bone marrow. As a pharmaceutical agent, this protein is used for the treatment of anaemia owing to the effect of concomitantly administered chemotherapy agents in cancer patients.

LOW MOLECULAR-WEIGHT HEPARIN

This is produced when heparin is cleaved to produce lower molecular-weight species, which are then purified.

GLYCOCONJUGATE

Glycans that are covalently attached to other biomolecules, such as proteins or lipids.

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Shriver, Z., Raguram, S. & Sasisekharan, R. Glycomics: a pathway to a class of new and improved therapeutics. Nat Rev Drug Discov 3, 863–873 (2004). https://doi.org/10.1038/nrd1521

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