We apply chemical principles, particularly those of organic chemistry, to solve problems focused on human health. Over the past few years, my group has worked in several areas including anti-DNA autoantibody structure and function, and the identification of novel molecular targets and small molecules for the treatment of autoimmune diseases and cancer.
Anti-DNA autoantibodies are a hallmark of the autoimmune disorder systemic lupus erythematosus, and mediate a kidney inflammation that can be fatal. However, the DNA molecules recognized by anti-DNA and their binding properties remain poorly understood. We have conducted chemical, biochemical, and genetic studies to investigate the interaction of pathogenic anti-DNA with ssDNA. Ultimately, we hope that characterization of anti-DNADNA interactions will provide insight to advance diagnosis of lupus.
In a second area, we are identifying new targets and small molecules for the treatment of autoimmune diseases and cancer. Current therapies for these disorders employ cytotoxic agents that have limited efficacy and serious side effects. Using diversity-oriented synthesis, we identified a class of non-anxiolytic, pro-apoptotic benzodiazepines that treat disease in animal models of lupus. These compounds selectively kill pathogenic lymphocytes, and unlike current therapies, they are not adversely immunosuppressive.
We are now exploring the signals that arise as a result of target binding. These studies should help to uncover the basis for the selectivity displayed by these compounds and help to delineate the specific signals that initiate apoptosis. Additionally, the target of our benzodiazepines is a relatively uncharacterized component of the mitochondrial F1F0-ATPase, and only limited information about its function within the enzyme is available. Therefore, we are also using these compounds to probe the function of this protein within the F1F0-ATPase using a combination of biology, organic synthesis, kinetics, and structural studies of targetdrug interactions.
We have discovered that our benzodiazepines circumvent the major mechanisms cancer cells use to become resistant to therapy. Based on our understanding of the factors regulating the cellular sensitivity to our agents, we plan to examine the effects of these compounds on resistant cancers. These experiments should demonstrate additional uses for these molecules and reveal new pathways and targets for additional drug discovery.
Bednarski, J.J., Lyssiotis, C.A., Roush, R., Boitano, A.E., Glick, G.D., Opipari, A.W. Jr., Bz-423 Increases the Sensitivity of B Cells to Receptor Stimulation with Synergistic Effects on Calcium Signaling and Apoptosis, J. Biol. Chem., 2004, 279, 29615.
J. Varani, N. Bhagavathula, H. Scherzer, K. Fay, G. D. Glick, K. Johnson, S. Kang, and A.W. Opipari, Jr., "Bz-423 Selectively Inhibits Keratinocyte Proliferation and Reduces Retinoid-Induced Epidermal Hyperplasia in Organ-Cultured Human Skin". J. Pharmacol. Exp. Ther. , 2005 , 313 , 56.
X. Chen, K.M. Johnson, A. Boitano, L. Swenson, A.W. Opipari, Jr, and G.D. Glick, "The Mitochondrial F 1 F 0 -ATPase is the Molecular Target of the Immunomodulatory Benzodiazepine Bz-423", Chem. Biol . 2005 , 12 , 485.
C.P. Price, G.D. Glick, and A.J. Matzger. "Dissecting the Behavior of a Promiscuous Solvate Former". Angew. Chem ., 2006 45 , 2062-66.
T. Sundberg, G.M. Ney, A.W. Opipari, and G.D. Glick, "The Immunomodulatory Benzodiazepine Bz-423 Depletes the Oncogene c-Myc by a Novel Post-Translatonal Mechanism", Cancer Res ., 2006 66 , 1755.
T. Francis. T. Sundberg, T. Gryndyke, J. Cleary, A. Opipari, and G.D. Glick. "Identification of Cytotoxic T Cell Selective 2,5-Benzodiones", Bioorg. Med. Chem. Lett ., 2006