Heparan sulfate

We synthesise heparan sulfate structures on dendritic cores as potential therapeutics and research the role of natural heparan sulfate in bone repair.

Heparan sulfate structure
Structural model of heparan sulfate

Heparan sulfate is a linear sulfated polysaccharide. This heterogeneous glycosaminoglycan is present at the surface and in the extracellular matrix of all animal cells. It has a number of essential roles in cell signalling and regulation.

Our research with this material involves:

  • multistep complex organic synthesis of small, specific heparan sulfate structures
  • attachment of these synthetic compounds to dendritic cores, in order to mimic the naturally-derived polymeric material
  • manufacture and characterisation of components of natural heparan sulfate
  • collaboration with biologists in New Zealand, Singapore and the United Kingdom for evaluation as therapeutics for Alzheimer’s disease and in bone repair.

Our natural heparan sulfate is derived from porcine mucosa, available as a by-product of the heparin manufacturing process.

Current projects

Current projects in this research area include:

  • structure-activity relationships
  • chemical modification and characterisation
  • applications in stem cell biology and in neurodegenerative diseases
  • support for GlycoSyn in the manufacture of clinical trial materials.

Some of these projects are suitable for postgraduate research projects, including Masters and PhD theses. Please contact Dr Alison Daines for more information.

Collaborators

University of Liverpool: Professor Jerry Turnbull
A-STAR*: Dr Simon Cool | Dr Victor Nurcombe

Staff

Dr Peter Tyler | Dr Simon Hinkley (programme leaders) | Dr Tracy Bell | Dr Susie Carnachan | Dr Ralf Schwörer | Dr Olga Zubkova

Heparan sulfate structures on dendritic cores

We have designed and synthesised oligosaccharides that mimic or interfere with the functions of heparan sulfate in biological systems.

This research (carried out in collaboration with Professor Jerry Turnbull) has previously been hindered by the complexity of the oligosaccharide synthesis. Our novel approach, however, has enabled us to rapidly create a library of single entity glycomimetic clusters capped with varied heparan sulfate saccharides.

These molecules model longer natural heparan sulfates and also inhibit the protease beta-secretase 1 (BACE-1). This activity prevents the build-up of beta-amyloid, which may help slow or stop Alzheimer’s disease.

We have identified several potent clusters that are drug leads for Alzheimer’s disease. The clusters also provide a way to study the interactions of heparan sulfate with proteins more generally.

References

Single entity heparan sulfate glycomimetic clusters for therapeutic applications, Angewandte Chemie International Edition (2015).

Synthesis of a targeted library of heparan sulfate hexa- to dodecasaccharides as inhibitors of β-secretase: potential therapeutics for Alzheimer’s disease, Chemistry - A European Journal (2013).

Bone repair

In an ongoing and close collaboration with Singaporean researchers, we have prepared a novel heparan sulfate material that significantly enhances bone healing. The material is placed in a trauma site on a collagen support and has high potency but very low toxicity. It shows remarkable improvement over the current therapies that are used to aid the repair serious bone damage.

This heparan sulfate material works by increasing the bioavailability, bioactivity and half-life of bone morphogenetic protein, a potent bone healing compound that is produced where there is bone trauma.

The material is isolated from commercially available heparan sulfate using a peptide-based affinity resin and is in development by A-STAR*, our biology collaborators.

Using our expertise in the analysis of complex polysaccharides, we have developed analysis methods to characterise the active components of the heparan sulfate material. This work aims to identify the key structural components that are responsible for the material’s biological activity.

References

Engineering a vascular endothelial growth factor 165-binding heparan sulfate for vascular therapy, Biomaterials (2014).
Affinity-selected heparan sulfate for bone repair, Biomaterials (2013).