An array of inflammatory diseases such as pulmonary emphysema, chronic bronchitis, cystic fibrosis, psoriasis, rheumatoid arthritis and others, are characterized by an influx of neutrophils, and the presence of mediators of inflammation and cytokines that serve as neutrophil chemoattractants. The recruitment and degranulation of neutrophils in inflammatory states results in the production of reactive oxygen species and the extracellular release of the serine proteinases elastase, cathepsin G and proteinase 3. Poor regulation of the activity of these enzymes because of depressed levels of their physiological protein inhibitors leads to the degradation of the major components of the extracellular matrix and, ultimately the onset of disease. The use of innovative strategies that seek to counteract the damaging effects of the renegade enzymes be reestablishing a proteinase/antiproteinase inhibitor balance constitutes the long-term objective of the proposed research. The use of a potentially universal heterocyclic scaffold in the design of mechanism-based inhibitors that endows these inhibitors with unique mechanistic features and optimal biochemical properties is proposed.
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