Jeanne A. Hardy

Professor of Chemistry, University of Massachusetts

Ph.D.: University of California at Berkeley

Research Interests

The Hardy Lab uses a combination of structural biology and chemical biology to discover and exploit allosteric sites on proteases of biomedical importance. We use biophysical tools such as protein crystallography, NMR and HDX-MS as well as chemical synthesis and characterization and a wide range of biochemical techniques. Our main research focuses on the caspase proteases, which are critical for controlling apoptotic cell death. We have made important contributions to understanding how natural processes (e.g. phosphorylation, nucleotides and zinc binding) and synthetic molecules can allosterically regulate each of five apoptotic human caspases in unique ways. Our structural characterization of these modifiers has enabled to us to compile a comprehensive map of allosteric regulation across the apoptotic caspases. Concurrent with that work, caspase-6 also emerged as a promising drug target for treating Alzheimer’s Disease. A large body of our work on caspase-6 has focused on defining a conformational transition that is unique to caspase-6, wherein a turn beneath the active site transforms to a helix that blocks the active site. Using our biophysical insights into this phenomenon, have developed a highly potent (33 nM) and selective (>500-fold) caspase-6 inhibitor . We have tested this inhibitor in animal models and have found that it indeed crosses the blood-brain barrier. This finding has prompted our continued development of this compound for clinical application. A second applied area of our caspase research involves delivery of various apoptotic caspases to cancer cells to induce cell killing that can be tuned to the proteome of the individual cancer. Intriguingly, we have found that the level of inhibitors of apoptosis proteins (or IAPs) are the most important predictor in which caspase will effectively kill which cancer cells. Our future investigations will continue to have both basic science and applied aspects in characterization of these proteases. A second research area in our lab centers on viral proteases. We have on-going investigations into the structure and function of the proteases from Dengue, Zika, West Nile flaviviruses, SARS-CoV-2 coronavirus, as well as proteases from the chikungunya and mayaro alphaviruses. Our characterization has explained why conformational changes are critical to flavivirus protease function and have allowed us to develop a 70 nM inhibitor that blocks Zika but not Dengue or West Nile proteases.