I am interested in developing drugs that give commands to either initiate or suppress specific biological actions. Such compounds, for example A3 receptor agonists, can correct an imbalance in the biochemical processes, associated with a disease, occuring inside cells in a given tissue or organ. They do this by adhering to members of a large family of receptors on the cell surface called G protein-coupled receptors (GPCRs). These receptors can transmit a chemical signal from the outside of a cell to the other side of the cell membrane, thereby activating pathways to produce cellular responses. It is important that we study these biological actions since they have the ability to correct an imbalance or turn on a natural protective function in a tissue. This is beneficial in disease states. My current focus is on receptors for purine, one of the building blocks for RNA and DNA.
I use biology, chemistry, and computer technology to study the chemical and biological aspects of GPCRs. As chemists, we can synthesize new target molecules of interest that are designed to have particular characteristics. We can then test these new molecules in biological systems. We often base these new molecules on substances that are known to have an effect on multiple biological targets. Our goal is to make these substances more selective so that, instead of having an effect on multiple biological targets, they only have an effect on a single receptor target.
My team uses many different tools in its work—including computer models, synthetic approaches, and methods to mimic how molecules behave. We also use mutagenesis—changing genetic information in a controlled manner—to produce a desired mutation. For example, we may alter a receptor in order to test if a substance may have potential as a therapy.
Substances my lab develops could help in the treatment of diseases that affect the central nervous, immune, and cardiovascular systems. They have also been effective in treatment models for glaucoma, cancer, stroke, and cardiac ischemia. Two of the molecules we worked with performed so favorably in animal models of disease that they are now being tested in human patients for treatment of autoimmune inflammatory diseases and liver cancer.
One purine our lab is focusing on in our research is adenosine. Adenosine acts as an important modulator of the activity of every organ in the body and is relevant to a wide range of physiological processes, from the central nervous system to the immune system and the endocrine system. Adenosine is produced as a breakdown product of ATP (the “energy currency” inside the cells). When adenosine and ATP exit the cell by various means, they can act as important protective chemical signals. Adenosine is present in the medium surrounding all cells in the basal (resting) state, but its concentration outside of the cell rises dramatically when stress to an organ or tissue occurs, such as ischemia, inflammation, and oxidative stress.
The adenosine receptors (ARs) are important control elements in maintaining health, often acting as a means of correcting an imbalance in the body or responding to a physiological need, such as delivering more blood to cardiac muscle in distress. Adenosine acts in several ways to correct the “set point”—a level that is normal in a tissue and that the body tries to maintain, like a furnace keeps a set temperature. Adenosine protects tissues throughout the body. We are studying compounds that bind to adenosine receptors as novel therapeutics. For example, agonists for the A3AR appear to be effective in treating autoimmune inflammatory diseases and cancer. We obtain clues about the structure of new compounds from compounds that are already known. We then make them more selective and potent.
To conduct these studies we use computer-based screening of chemically diverse libraries along with structure-based drug discovery. We aim to understand how changes in the molecular structure of these small molecules alter the receptor subtype selectivity. Screening methodology, such as the introduction of new fluorescent methodology, is also being developed.