Mammalian and viral protease inhibitors

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Dou, Dengfeng
Groutas, William C.

Chronic Obstructive Pulmonary Disease (COPD) is currently the fourth leading cause of death in the US. COPD is a multi-factorial disorder characterized by an oxidant/antioxidant imbalance, inflammation, a protease/antiprotease imbalance and apoptosis. This dissertation describes a general strategy for the design, synthesis and biochemical evaluation of dual function inhibitors which could potentially interrupt the above disorder, thereby enhancing the treatment of COPD. An example of this type inhibitor based on the 1,2,5-thiadiazolidin-3-one scaffold has been proven effective against both human neutrophil elastase (HNE) and caspase-1, two key enzymes responsible for elastin degradation and inflammation, respectively. In addition, an X-ray crystal structure and a high resolution mass spectrum of inhibitor bonded HNE have proven the proposed mechanism of HNE inactivation. Furhtermore, simple reversible competitive inhibitors of COPD-related enzymes (HNE and proteinase 3) have also been designed, synthesized and evaluated biochemically. West Nile virus and Dengue virus are recognized as a major health threat that affects millions of people worldwide. However, there is currently no treatment or vaccine available for the virus infection. This dissertation describes the design, synthesis and biochemical evaluation of reversible competitive inhibitors of both West Nile virus and Dengue virus NS2B-NS3 protease. Combinatorial chemistry and click chemistry methods have been used in the design of the protease inhibitor and the identified hit was optimized using computational programs (AutoDock4 and SYBYL). Several more hits were identified during the optimization and further development could potentially lead to very potent inhibitors of NS2B-NS3 protease with good pharmacokinetics and oral bioavailability.

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Thesis (Ph.D.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry