Emerging Principles for the Therapeutic Exploitation of Glycosylation

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Science  03 Jan 2014:
Vol. 343, Issue 6166, 1235681
DOI: 10.1126/science.1235681

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Structured Abstract


Glycoproteins and glycolipids exist as an ensemble of glycosylated variants, or glycoforms. Specific glycoforms are directly modulated by microenvironmental cues and play a key role in a wide spectrum of biological processes. Consistent with this, certain glycoforms are also prominent in various pathological conditions. These structures are either targeted by exogenous pathogens or associated with specific disease stages or, in some cases, their aberrant expression acts as a trigger to a particular disorder. An increased molecular and structural understanding of the mechanistic role that specific glycoforms play in these pathological processes has driven the development of therapeutics and illuminated novel targets for drug design.

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Antibody glycosylation determines Fc functions. An example is the removal of an antibody’s Fc glycans (red, green, and blue) by a bacterial immune evasion factor, endoglycosidase S, which impedes Fc engagement with cellular receptors (orange) and therefore immunological effector cells.


Intervening in cellular glycosylation pathways provides a route to the alleviation of many of the symptoms of congenital metabolic disorders. Some of these same drugs also affect glycan-mediated virion assembly and offer an exciting prospect for the development of broad-spectrum antivirals against enveloped viruses. Further stages of the viral replicative cycle can be disrupted by considering their dependence on glycosylation, and this currently forms the basis of anti-influenza drugs and potential new classes of anti-inflammatories. The development of therapeutic glycoproteins has been greatly stimulated by the advances in recombinant cellular biosynthetic technologies that can produce defined glycoforms. A prominent example of this approach is the development of monoclonal antibodies with engineered glycosylation, which display enhanced in vivo properties. Furthermore, antibody glycosylation can also be directly modulated in vivo. Serum antibodies involved in autoimmunity can be inactivated by removal of their glycans by bacterial immune evasion factors, and this technology has shown great promise in preclinical studies. Glycopeptides offer intriguing possibilities in the development of anticancer vaccines given their ability to stimulate both humoral and cellular immunity. Additionally, the HIV glycan shield is proving to be an effective target for antibody neutralization and emerging targets for vaccine design and control of infection.


Antiviral therapy looks set to have a strong glycan component in the near future. Viral protein-folding inhibition by monosaccharide analogs and glycan-epitope–dependent antibody neutralization are both promising areas. Although a successful glycan-based vaccine to cancer or HIV has yet to be realized, recent advances in both glycopeptide immunization and elucidation of the unusual features of broadly neutralizing antibodies have provided fresh impetus to these goals. Glycan engineering will continue to deliver enhanced therapeutic glycoproteins, such as antibodies, with enhanced disease modifying properties. Last, the application of bacterial enzymes that cleave antibody glycans may offer new therapeutic opportunities.

Understanding Glycosylation

Glycosylation—the covalent addition of carbohydrates to proteins—is central to many biological processes. Recent advances in understanding the roles of glycans—for example, in protein folding and immune regulation—have revealed that glycans are also involved in many disease conditions, from cancer to microbial infection. Dalziel et al. (p. 10.1126/science.1235681) review the current knowledge of glycans in pathogen invasion, cancer, autoimmunity, and congenital diseases.


Glycosylation plays a key role in a wide range of biological processes. Specific modification to a glycan’s structure can directly modulate its biological function. Glycans are not only essential to glycoprotein folding, cellular homeostasis, and immune regulation but are involved in multiple disease conditions. An increased molecular and structural understanding of the mechanistic role that glycans play in these pathological processes has driven the development of therapeutics and illuminated novel targets for drug design. This knowledge has enabled the treatment of metabolic disorders and the development of antivirals and shaped cancer and viral vaccine strategies. Furthermore, an understanding of glycosylation has led to the development of specific drug glycoforms, for example, monoclonal antibodies, with enhanced potency.

  • This article is dedicated to Chris Scanlan, who passed away after a short battle with cancer during the writing of this article.

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