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    Mechanism-based inactivation of humam neutrophil elastase

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    Thesis (877.1Kb)
    Date
    2008-12
    Author
    Li, Yi
    Advisor
    Groutas, William C.
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    Abstract
    Chronic obstructive pulmonary disease (COPD) is a major health problem that affects 16 million people in the US, and is currently the fourth most common cause of death. Although the pathogenesis of COPD is poorly understood, current studies indicate that COPD is a multi-factorial disorder characterized by a cigarette smoke-induced cycle of oxidative stress, alveolar septal cell apoptosis, a protease/antiprotease imbalance, and chronic inflammation. An array of serine (HNE, PR3), cysteine (cathepsin S), and metallo- (MMP-1, MMP-9, MMP-12) proteases released by neutrophils, macrophages, and T lymphocytes contribute to the degradation of lung connective tissue and mediate a multitude of signaling pathways associated with the pathophysiology of the disorder. Re-establishment of a protease/antiprotease balance by utilizing potent and selective protease inhibitors is a promising approach for the development of potential therapeutics for COPD. We describe herein the design, synthesis and biochemical evaluation of a novel class of mechanism-based inhibitors of HNE that exploit the catalytic machinery of the target enzyme to generate a Michael acceptor. Subsequent reaction with an active site nucleophilic residue leads to inactivation of the enzyme. A noteworthy feature of the inhibitors is their ability to interact with the S1-Sn’ subsites of the target enzyme.
    Description
    Thesis (M.S.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry

    Includes bibliographic references (leaves 42-46)
    URI
    http://hdl.handle.net/10057/2099
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