New Method for Mapping Drug Structure and Function

Sugars are found everywhere in nature and are essential for life. In humans, they cover the surface of all cells. However, one family of polysaccharides, GAGs (glycosaminoglycans), are particularly abundant and difficult to analyze.

GAGs of the heparan sulfate type play key roles in regulating many biological functions, including inflammation, neurodegeneration, and tumor metastasis. In fact, a special type of heparan sulfate called heparin can prevent coagulation and is currently one of the most used drugs in the clinic. Researchers are therefore intensively trying to map the detailed structures of heparan sulfates and link them to their biological functions.

So far, only a few structures have been successfully identified, but that may be about to change. In a University of Copenhagen study published today in Nature Communications, researchers invented a new method that will boost the mapping of these structures.

“Determining the structures is a key question in the research about sugars,” says first author Rebecca Miller. “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.”

The researchers’ new method is called “Shotgun ion mobility mass spectrometry sequencing” (SIMMS2). The technique relies on advanced mass spectrometry to break the sugar structures into smaller fragments, separate them, and fingerprint them compared to known standards. Virtual reassembly of the sugar pieces into a picture of the original sugar can then determine larger sequences of polysaccharides that are big enough to capture the cues that direct functions like anti-coagulation.

The GAG team at Copenhagen Center of Glycomics recently reported the first cell-based method (GAGOme) to produce all variants of GAGs for discovery of functions and development of therapeutics (Chen et al, Nature Methods 2018), and this will be combined with the new method for sequencing of GAG structures. The hope is to follow up on many promising therapeutic effects of heparins in cancer and neurogenerative diseases and pioneer new applications of GAGs in medicine.

The researchers also plan to apply their method to understand heparan sulfate structural cues that regulate stem cells to generate specialized neurons for treatment of Parkinson’s disease.