Pulmonary emphysema is currently believed to accure as a result of a proteinase-proteinase inhibitor imbalance in the lungs. The proteinases that are believed to be responsible for the degradation of lung connective tissue are neutrophil elastase and cathepsin G. Re-dressing the proteinase-proteinase inhibitor imbalance is a quest of paramount scientific and therapeutic importance. In principle, this can be accomplished through the use of potent and biospecific inhibitors of the target enzymes. The specific objectives of the research are: (a) the rational (biochemically-based) design and synthesis of mechanism-based inhibitors of leukocyte elastase and cathepsin G. The design of the inhibitors is based on the Lossen rearrangement; (b) in vitro studies aimed at ascertaining the efficacy and biospecificity of the inhibitors; (c) biochemical studies including elucidation of the mechanism of action of the inhibitors, probing the make up of the active sites of the target enzymes, in vitro stability studies, determination of deacylation rates, stereochemical studies etc.; and (d) in vivo pharmacological studies to evaluate the efficacy and toxicity of the synthesized compounds. Understanding the biochemical basis underlying emphysema and the development of therapeutic agents for pulmonary emphysema and related ailments constitute the long-term goals of the research.
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