Reengineering the sugar forest
Researchers at Leeds are hijacking a nasty strain of the bacteria that causes cholera to create a delivery system for treating neurological disorders. However, they are avoiding the bacterial toxin that actually causes cholera symptoms; instead, they focus on the protein that facilitates the toxin's entry to our intestinal cells.
This protein has some very useful properties. When injected into a muscle, it will attach to sugars found on the surface of nerve cells, using them to travel through these cells right into the central nervous system in the spine.
Professor of Biomolecular Chemistry Bruce Turnbull explains: “It’s normally very difficult to get drugs into the central nervous system, particularly large molecule drugs that can’t pass the blood brain barrier, but this protein opens up a back door. Working with Professor Jim Deuchars in Biological Sciences, we’re re-engineering the protein to carry drugs, rather than the toxin, so that we can deliver treatments for neurological diseases right to the heart of the nervous system.”
Cholera toxin is just one of the bacterial and viral proteins that Professor Turnbull and his colleagues, Dr Michael Webb and Professor Dejian Zhou, are adapting to act as drug delivery systems and for use in diagnostics and vaccines.
We’re re-engineering the protein to carry drugs, rather than the toxin, so that we can deliver treatments for neurological diseases right to the heart of the nervous system.
Cell surface sugars
Much of their research focuses on the sugars that cover the surface of every living cell, through which viruses and bacteria have to navigate if they want to enter and infect it. Professor Turnbull describes the structures these sugars make as a ‘forest’ on the cell surface.
The sugar forest has three layers. The biggest ‘trees’ are long strings of sugar molecules, known as glycosaminoglycans, that extend way above the cell surface. Below this are smaller trees known as glycoproteins: proteins with a glycan or sugar molecule attached to them. And finally, the cell membrane or forest floor is covered with lower lying undergrowth: glycolipids, which are fats with a glycan attached.
Much of the research at Leeds involves the smaller trees and undergrowth in the forest - the glycoproteins and glycolipids – which are the sugars that bacterial proteins in particular tend to attach to.
Diagnostics and vaccines
In a project involving eight different universities, the Leeds researchers have been creating a range of synthetic glycans that will consistently bind to specific bacterial toxin proteins, opening up the possibility of a diagnostic tool for a range of bacterial infections.
The Leeds researchers harness the power of nature to create these synthetic sugars. Chemical modification of cell surface sugars is complex and inefficient, so instead the team use natural enzymes, which our bodies make to modify proteins and sugars and join them together.
The challenge is to make these natural enzymes work with our synthetic glycans, and that’s where a lot of our research is focused.
“The challenge is to make these natural enzymes work with our synthetic glycans, and that’s where a lot of our research is focused,” explains Professor Turnbull.
Ensuring consistency in the way that the glycans and proteins are linked together is also key to enabling mass production of any treatments or vaccines based on these synthetic molecules.
Professor Turnbull says, “Our immune systems respond most strongly to proteins, so to create an immune response to a bacterial glycan, it needs to be attached to a protein. But not in any random way – it’s important that the two molecules are attached in the same way, all the time.”
Although ensuring this consistent binding is not an easy feat, it’s one that Professor Turnbull and his team have mastered with the help of a bacterial enzyme called sortase. Sortase is used by the bacterium Staphylococcus aureus to attach proteins to its cell wall and the team have exploited this property for their own use. Their hope is that this technique could provide a means of developing more effective vaccines against infectious diseases.
If you would like to know about this area of research in more detail, please contact Professor Bruce Turnbull.