I am interested in a basic control system in the body that has relevance for the treatment of diverse diseases and chronic conditions. This system is regulated by signaling molecules outside the cell that act by homing in on specific proteins on the cell surface called receptors. We mimic or block these signaling molecules with compounds synthesized in our lab to target the receptor. When such a compound adheres to its receptor it gives a command to the cell to either initiate or suppress specific biological actions.
These signaling molecules are related to adenosine and ATP (adenosine triphosphate, the “energy currency” inside the cells), which occur naturally and are released by cells. Adenosine can be produced as a breakdown product of ATP. Adenosine is present in the medium surrounding all cells in the resting state, but its concentration outside of the cell rises dramatically when stress to an organ or tissue occurs, such as insufficient oxygen and inflammation. Adenosine and ATP-like molecules act as important modulators of the activity of every organ in the body and are relevant to a wide range of physiological processes, from the central nervous system to the immune system and the endocrine system. 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.
We are designing, preparing and studying new chemical compounds that bind to these receptors both as research tools and potentially as novel therapeutics. For example, activators of one of the four members of the AR family, called the A3 subtype, which were invented in our lab, appear to be effective in clinical trials for treating autoimmune inflammatory diseases (rheumatoid arthritis and psoriasis) and primary liver cancer.
My team uses many different tools in its work—including computer models, chemical synthetic approaches, and genetic methods to probe how molecules behave. We are also developing methodology, such as fluorescent tracer compounds, for screening molecules in the discovery of new pharmaceutical lead molecules. We also use mutagenesis of the drugs’ protein targets 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 compound may have a therapeutic potential. Altogether, we use biology, chemistry, and computer technology to study the chemical and biological aspects of receptors. As chemists, we can synthesize new 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 compounds that are known to have an effect on multiple biological targets. Our general goal is to make these compounds more selective so that, instead of having an effect on multiple biological targets, they only have an effect on a single type of receptor. Sometimes the receptor can be activated in a nuanced fashion to activate only certain processes inside the cell and not others normally associated with that receptor. New compounds that produce this type of activation, called “biased”, is also within the scope of our research program.
We often obtain clues about the structure of new compounds that do a specific job in the body from compounds that are already known in that context. We can improve upon the effectiveness of the natural substance. Other times, we discover the potential of a molecule from an unrelated class to fulfill this biological need. We then make them more selective and potent by changing the chemical structure appropriately in a systematic fashion. So we know the effects on the activity of changing specific parts of the molecule – and this can sometimes be predicted by computer modeling. Some of our new molecules demonstrate beneficial effects in cell or animal models of disease and therefore we consider how to advance these compounds toward clinical use. Usually we base this work on a concept that is so innovative that the pharmaceutical industry would consider it too risky to touch. Thus, our basic research can eventually have a practical outcome to benefit patients. This is very challenging, because of the complexity of interactions of new molecules in the body and the many way in which lack of side effects and other safety criteria must be demonstrated. Compounds my lab develops could help in the treatment of conditions such as glaucoma, cancer, stroke, thrombosis, cardiac ischemia and diabetes, in addition to diseases mentioned above.