New method for mapping the structures of heparan sulfate sugars

Heparin, the blood-thinning drug, is used worldwide. However, to date, mapping of the fundamental sugar structures of heparin and the wider class of heparan sulfate sugars in cells has not been accomplished.

Image Credit: University of Copenhagen.

A team of scientists led by Dr. Rebecca Miller at the University of Copenhagen—a recent recruit from the United Kingdom—has now formulated a technique to map the sugar structure of this type in detail. This technique has a huge potential to unravel significant biological functions and to enable the development of new drugs.

Sugars such as polysaccharides are omnipresent and are considered essential for life to exist. In humans, the surface of all cells are covered by these sugars, and the class of polysaccharides known as glycosaminoglycans (GAGs) are challenging to analyze.

Heparan sulfate-type GAGs play a significant role in controlling several biological functions, such as neurodegeneration, inflammation, and tumor metastasis.

A unique type of heparan sulfate known as heparin is one of the drugs frequently used in the clinic to prevent coagulation. Scientists are making considerable efforts to map the comprehensive structures of heparan sulfates and connect them with their biological functions.

To date, only a few structures have been identified successfully, but there are chances for changes to occur. Rebecca and her colleagues formulated a new approach to optimize the mapping of these structures.

This method has been reported in a new study from the Danish National Research Foundation Centre for Glycomics at the Department of Cellular and Molecular Medicine, the University of Copenhagen, published in the journal Nature Communications.

Determining the structures is a key question in the research about sugars. If we know the structure, we can determine what the cues are for specific biological functions and consider potential ways to exploit this in the development of therapeutics. This is hugely important and clinically relevant, as shown by the widely used anti-coagulant heparins, and the potential application of new heparin-based drugs for multiple diseases in the future.”

Dr Rebecca Louise Miller, Study Corresponding Author and Assistant Professor, Copenhagen Center for Glycomics

New technology and new EU funding

The scientists’ new technique is termed “Shotgun ion mobility mass spectrometry sequencing” (SIMMS), which depends on advanced mass spectrometry to disintegrate the sugar structures into smaller fragments, separate them, and fingerprint them in comparison with already established standards.

Through the virtual reassembly of the sugar pieces into an image of the original sugar similar to solving a big jigsaw puzzle—only infinitely more complicated—for the first time, larger sequences of polysaccharides that are sufficiently large to capture the signals that manipulate functions like anti-coagulation can be identified.

The instrumentation behind this new method was invented by the company Waters Ltd in 2006 and is available to many pharmaceutical companies and researchers. This means that the method could be easily implemented and widely used for drug discovery by many research groups in a short period of time.”

Jeremy Turnbull, Study Co-Author and Professor, University of Liverpool

Turnbull is also a professor at the Copenhagen Center for Glycomics, where the GAG team recently reported the first cell-based technique called GAGOme to generate all variants of GAGs to unravel the functions and development of therapeutics (Chen et al., Nature Methods, 2018). This will be integrated with the new approach for sequencing the GAG structures.

The researchers aim to monitor several potential therapeutic effects of heparins in cancer and neurogenerative diseases and to explore the new applications of GAGs in the field of medicine.

Miller and Turnbull were recently awarded an EU grant of €3.8m to continue the advancement of the SIMMS method and explore new applications of GAGs in medicine. The grant was awarded to a consortium that also included researchers from Freie Universität Berlin, University of Utrecht, University of Liverpool, and Karolinska Institute in Stockholm.

Moreover, the method will be applied to gain insights into heparan sulfate structural cues that are used to manipulate stem cells to create specialized neurons to treat Parkinson’s disease.

Researchers from the Freie University Berlin in Germany and the Universities of Oxford and Liverpool in the United Kingdom also contributed to the study.