Grant: Foundation Grant

The surfaces of every cell in the human body are coated with specific sugars. These play several roles, principally providing a way for the cell to interact with other cells and their components. Invading bacteria and viruses also use these sugars as an entry point, thus an understanding of these interactions and of how the specific sugars are built and degraded, can lead to new therapeutics. An example is the influenza virus drug Tamiflu, which blocks the critical viral enzyme that cuts a sugar off our cell surfaces and allows the virus to spread. Our recent research has shown that some of the enzymes used by disease-causing bacteria and parasites in order to infect human cells are unlike any enzymes present in human cells. This allows us to design and synthesize new classes of drug to either specifically block these enzymes, as with Tamiflu, or to liberate toxins specifically within the invader. Using such approaches, in collaboration with microbiologists, we shall develop new strategies for treatment of antibiotic-resistant bacteria, as well as the parasites that cause Chagas disease in South America. In a second part of our work we shall use enzymes to modify these cell surface sugars for a variety of applications. In one case we use enzymes to cut specific sugars off the surface of red blood cells, thereby changing their blood type from A or B (or AB) to the "universal donor" Type O. Using an approach that mimics the process of natural evolution, but accelerates it, we shall engineer these enzymes to speed them up for clinical use. This work should greatly improve our supply of blood for transfusions. In a second case we shall use enzymes to improve the performance of increasingly important protein-based drugs such as antibodies and growth factors. Most such proteins have sugars on their surface that play important roles. We shall engineer enzymes to add sugars in a highly controlled manner, yielding drugs of improved performance.