Sugar-coating the search for new therapeutics
Do you remember when the Atkins diet was a fad? Maybe I’ve just dated myself, but at the height of its popularity in the early 2000’s, almost 10% of North Americans reportedly followed a low-carb diet. When I began my PhD studies in Canada a few years later studying ‘carbohydrates’, I was often asked about the latest Atkins-type trends, which unfortunately I know nothing about. In all honesty, given my weekly consumption of fondue upon moving to Switzerland (whoever claims that fondue has a season is arguably wrong), I am the last one that you want to be coming to for diet advice.
What many people are not aware of is that carbohydrates — which is actually just a scientific term describing ‘sugars’ — form a dense coating around all of our cells. And not just human cells. They coat every type of cell that people have ever identified: bacteria, viruses, plants, etc. On several cell types, such as those lining our blood vessels, this carbohydrate layer is over 100 times thicker than the lipid bilayer!
Friend or foe? Sugars at the cell surface
What is the purpose of these cell-surface carbohydrates? The molecular composition of this carbohydrate layer varies across different species, tissues, and age of the cell. As a result, our immune cells rely heavily on this carbohydrate ‘barcode’ to determine whether each cell they encounter is from ourselves, an invader, or even whether it is healthy or diseased. If immune cells detect an invading cell, they release chemical signals that lead to destruction of the invader. If it recognizes our own carbohydrates, then it just moves along in search of another cell to inspect.
In fact, these different sugar structures are the origin of our A, B, and O blood types. The A, B, and O designations refer to three distinct carbohydrate structures that are found at the surface of blood cells. If you transfuse a patient with blood cells that have a carbohydrate structure different from the one that their own body naturally produces, the immune system sees these cells as unwelcome invaders which leads to their rapid destruction.
Although carbohydrates typically keep our own cells safe from immune system attack, they can also work against us. For instance, after an organ or tissue has suffered from reduced blood flow (heart attack, stroke, etc), cells in the tissue change their carbohydrates to indicate that they are damaged. These new carbohydrate structures can cause the damaged tissue to be targeted by immune cells, adding further insult to the injury. This also occurs in organ transplantation, and is an important cause of transplant rejection.
Pathogens with a sweet-tooth
These cell-surface carbohydrates are also exploited by infectious pathogens. For instance, Escherichia coli strains associated with urinary tract infections use carbohydrate-binding proteins to firmly attach to bladder cells to avoid being flushed out when we urinate. Or consider the influenza viruses, which only infect cells coated with a particular carbohydrate structure. In fact, the naming of different influenza strains, such as H1N1 that we became so familiar with in 2009, is based on two different carbohydrate-associated proteins: hemagglutinin (H) which binds to a particular carbohydrate structure and enables viral entry into the cell, and neuraminidase (N) which removes a cell-surface carbohydrate and frees the virus to migrate and infect adjacent cells.
Even SARS-CoV-2 and other coronaviruses are known to utilize carbohydrates for viral entry into cells. And viruses have also figured out how to use these carbohydrates against us. They are masters at mimicking our own structures to avoid detection by immune cells.
Sugars as therapeutics
Most of what we know about cell-surface carbohydrates has been discovered in the last 30 years, a fortunate consequence of improved technologies that have enabled us to identify discrete carbohydrate structures, which are notoriously difficult to isolate and characterize.
Learning more about these interactions, our team within the Department of Pharmaceutical Sciences at the University of Basel is interested in applying this knowledge to develop new drugs. Sugars themselves are not suitable drug candidates, as they are rapidly metabolized and eliminated from the body when not attached to a cell-surface. Thus, our research involves the development of carbohydrate-based mimetics, which can retain biological activity but have improved ‘drug-like’ properties. For example, in organ transplantation we can design carbohydrate-based molecules which prevent immune cells from recognizing transplanted tissue. Using a similar approach, we can design inhibitors to occupy protein binding sites so that pathogens can no longer adhere to or infect host cells, offering a ‘sweet’ alternative to traditional antibiotics.
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