Date of Award

1-1-2009

Document Type

Campus Access Dissertation

Department

Chemistry and Biochemistry

Sub-Department

Chemistry

First Advisor

Paul R. Thompson

Abstract

The family of Protein Arginine Deiminases (PADs) include five mammalian isozymes (PAD1, 2, 3, 4, and 6) that catalyze the post-traslational modification of peptidyl-arginine to peptidyl-citrulline in numerous protein substrates. This modification results in numerous physiological and pathophysiological changes that are believed to play a significant role in the onset and progression of several diseases, e.g., cancer, multiple sclerosis, and rheumatoid arthritis. In particular, there is mounting evidence that suggests dysregulated PAD4 activity plays a critical role in the pathogenesis of Rheumatoid Arthritis (RA). RA is an autoimmune disorder characterized by chronic inflammation of the joints. Currently, RA therapeutics are insufficient because they focus on alleviating the symptoms and avoid an underlying cause of the disease. For this reason, we have focused on developing PAD4 inhibitors in an effort to reduce protein citrullination in the joints as a potential RA therapeutic. Recently, the design and synthesis of PAD4 inhibitors, F- and Cl-amidine, has been described. Herein, we have characterized the catalytic mechanisms of PADs 1, 3, and 4 by kinetic analysis and have identified the mechanism of PAD inactivation by F- and Cl-amidine. Furthermore, the goal of identifying novel lead compounds for inhibiting PAD4 activity has led to the development of two novel high-throughput screens for identifying PAD4 inhibitors. In addition, the therapeutic efficacy of Cl-amidine for the treatment of RA has been evaluated in mice. In total, the information collected will aid in the design of future PAD inhibitors that are more potent and selective.

Rights

© 2009, Bryan Knuckley

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