Pulmonary emphysema is currently believed to accrue as a result of a proteinase/proteinase inhibitor imbalance in the lungs. The proteinases that are believed to be primarily responsible for the degradation of lung connective tissue are neutrophil elastase and cathepsin G. Other neutrophil enzymes that play a role in the disease are proteinase-3, cathepsin L, and myeloperoxidase. The long-term goal of the proposed research is the elucidation of the biochemical basis underlying pulmonary emphysema and the development of effective therapeutic interventions through the modulation of the activity of the enzymes implicated in the pathogenesis of the disease. The specific objectives of the proposed research are the following: a) the biochemically-based design and synthesis of inhibitors of the serine proteases leukocyte elastase, cathepsin G and proteinase-3. The design of the inhibitors is based on the Lossen and Gabriel-Colman rearrangements and will be aided by molecular graphics and modeling. b) in vitro biochemical studies aimed at determining the efficacy, mechanism of action, biospecificity and stability of the inhibitors. These studies will also include the mapping of the active site of proteinase-3 (to be done in collaboration with Dr. John Hoidal, University of Utah Health Sciences Center). c) in vivo pharmacological studies to evaluate the efficacy and toxicity of the synthesized compounds (to be done in collaboration with Dr. George Weinbaum of The Graduate Hospital, Philadelphia).
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