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  • Review Article
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The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans

Nature Reviews Drug Discovery volume 20, pages 217–243 (2021) Cite this article

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An Author Correction to this article was published on 08 February 2021

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Abstract

Carbohydrates — namely glycans — decorate every cell in the human body and most secreted proteins. Advances in genomics, glycoproteomics and tools from chemical biology have made glycobiology more tractable and understandable. Dysregulated glycosylation plays a major role in disease processes from immune evasion to cognition, sparking research that aims to target glycans for therapeutic benefit. The field is now poised for a boom in drug development. As a harbinger of this activity, glycobiology has already produced several drugs that have improved human health or are currently being translated to the clinic. Focusing on three areas — selectins, Siglecs and glycan-targeted antibodies — this Review aims to tell the stories behind therapies inspired by glycans and to outline how the lessons learned from these approaches are paving the way for future glycobiology-focused therapeutics.

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Fig. 1: Selectins and their primary ligands.
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Fig. 2: P-selectin engages both glycan and protein portions of PSGL1.
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Fig. 3: Small-molecule selectin inhibitors.
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Fig. 4: Siglecs and downstream signalling.
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Fig. 5: Modalities for Siglec-targeted therapies.
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Fig. 6: Tumour-associated carbohydrate antigen vaccines.
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Fig. 7: Timeline of key developments in translational glycobiology.
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Acknowledgements

Work from the authors’ laboratory was supported by a grant from the National Institutes of Health (CA227942). B.A.H.S. was supported by a Predoctoral Fellowship from the National Institutes of Health (F30CA232541) and the Stanford School of Medicine Medical Scientist Training Program. The authors thank M. Gray and S. Wisnovsky for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Chemical & Systems Biology and ChEM-H, Stanford School of Medicine, Stanford, CA, USA

    Benjamin A. H. Smith & Carolyn R. Bertozzi

  2. Department of Chemistry, Stanford University, Stanford, CA, USA

    Carolyn R. Bertozzi

  3. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA

    Carolyn R. Bertozzi

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Correspondence to Carolyn R. Bertozzi.

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C.R.B. is a co-founder of Redwood Bioscience, Enable Biosciences, Palleon Pharmaceuticals, InterVenn Bio, Lycia Therapeutics and OliLux Biosciences, and a member of the Board of Directors of Eli Lilly. B.A.H.S. is a shareholder of GlycoMimetics.

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Related links

Consortium for Functional Glycomics: https://functionalglycomics.com

GlyCosmos: https://glycosmos.org

GlyGen: https://glygen.org

Glossary

Glycoproteins

Proteins that are covalently conjugated to one or more glycans. These glycans may be either N-linked (connected to asparagine) or O-linked (connected to serine or threonine).

Proteoglycans

Glycoconjugates comprising a core protein decorated with glycosaminoglycans, which are long, linear chains of repeating disaccharides that are frequently sulfated. The sugars constituting this repeating unit are characteristic of different glycosaminoglycans. For instance, repeating N-acetylgalactosamine (GalNAc) and glucuronic acid (GlcA) distinguish chondroitin sulfate, whereas heparan sulfate begins as repeating N-acetylglucosamine (GlcNAc) and GlcA before undergoing heavy modifications, such as epimerization to IdoA and sulfation.

Catch bonds

Bonds that prolong their lifetime in response to increased tensile forces. By contrast, the lifetime of a slip bond decreases in response to higher tension.

Leukocyte extravasation

The process by which cells move from the circulation, across the blood vessel wall and into tissue parenchyma. Extravasation is a stepwise process beginning with rolling adhesion, then tight binding of leukocytes to the endothelium and, finally, diapedesis, where cells cross the endothelial barrier.

5xFAD mouse model

A mouse model for Alzheimer disease. 5xFAD mice express human amyloid protein precursor (APP) and presenilin 1 (PSEN1) along with five mutations in these genes linked to Alzheimer pathology.

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Smith, B.A.H., Bertozzi, C.R. The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans. Nat Rev Drug Discov 20, 217–243 (2021). https://doi.org/10.1038/s41573-020-00093-1

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