The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

The utility of small molecules that bind strongly and selectively to biological targets is unquestioned. These compounds have a variety of uses, from therapeutic drugs employed in the treatment of disease, to biological 'reagents' that aid in the elucidation of cellular pathways. The goal of our laboratory is to identify small molecules with novel biological functions, with a keen eye toward modulating and ultimately controlling a variety of disease states. To do this we use a diverse range of techniques, from molecular biology, enzyme assay development, and mammalian cell tissue culture, to synthetic organic and combinatorial chemistry. There are currently three main areas of interest:

Small molecule modulators of programmed cell death. Apoptosis, or programmed cell death, is a natural mechanism that multi-cellular organisms use to rid themselves of unwanted or damaged cells. Given its central role in both development and maintenance, when apoptosis goes awry there are disastrous consequences for the organism. Indeed, it has recently been estimated that over 50% of all diseases for which there are no cure are due to apoptotic mis-regulation. We are in the process of identifying small, cell-permeable, drug-like compounds that modulate apoptosis. Recently, we identified from a combinatorial library a small molecule that induces apoptosis in cancer cells but has virtually no effect on normal cells (see figure). We are in the process of creating more potent cell death inducers and using these compounds both as potential anti-cancer agents and as probes to study apoptosis. Conversely, compounds that inhibit cell death hold great promise for the treatment of neurodegenerative disorders. In this vein, we are developing isozyme-specific inhibitors of the caspases and of the enzymes involved in poly(ADP-ribosyl)ation. We will then use such compounds in cell culture models of neurodegeneration and in transgenic mouse models of Parkinson's disease, Huntington's disease, and ALS.

Novel approaches towards multi-drug resistant bacteria. Bacterial resistance to commonly prescribed antibiotics is a trend that has emerged over the last several decades and now constitutes a major public health crisis. In particular, multi-drug resistant bacteria such as methicillin-resistant Staphlococcal aureus (MRSA) and vancomycin-resistant enterococci (VRE) commonly infect hospital patients and in some cases have leapt into the larger community. The specter of VRE is particularly frightening as vancomycin is generally regarded as the last line of defense in the antibiotic arsenal. To effectively fight the widespread antibiotic resistance phenomena new strategies and novel targets are needed. My laboratory is attempting to create novel molecules that target machinery specific to multi-drug resistant bacteria. We have recently shown that certain facets of drug-resistant plasmids make them vulnerable to attack by small molecules, and we have identified compounds that cause plasmid elimination from bacterial cells. Through this project we are deeply involved in creating a general paradigm for small molecule-RNA binding, with the ultimate goal being the selective targeting of individual mRNAs within the cell.

Development of Novel Bio-Catalysts. Enzymes are nature's catalysts and offer multiple advantages over man-made catalytic agents. Unfortunately, their synthetic utility is currently limited to reactions that are catalyzed by naturally occurring enzymes. My laboratory is developing methods to rapidly convert existing enzymes into proteins that catalyze reactions of interest to synthetic organic chemists. For example, the Mannich reaction is a highly useful carbon-carbon bond forming reaction. Although there is no known enzyme that catalyzes this transformation, enzymes that catalyze the related aldol reaction have been described. We have designed a selection-based protocol that will allow us to identify interesting bio-catalyst for the Mannich and other reactions.