Protease inhibitors in respiratory disease: focus on asthma and chronic obstructive pulmonary disease

Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are a major health burden on society and current treatment modalities for these diseases have not significantly changed over the past 40 years. The only major pharmacological advancement for the treatment of these diseases has been to increase the duration of action of bronchodilators (asthma: salmeterol; COPD: tiotropium bromide) and glucocorticosteroids (asthma: fluticasone propionate) and, increasingly, to formulate these agents in the same delivery device. Despite our increasing understanding of the cell and molecular biology of these diseases, the development of novel treatments remains beyond the reach of the scientific community. Proteases are a family of proteins with diverse biological activity, which are found in abundance within the airways of asthma and COPD, and have been implicated in the pathogenesis of these diseases. The targeting of proteases, including mast cell tryptase, neutrophil elastase and matrix metalloprotease with low-molecular-weight inhibitors, has highlighted the potential role of these enzymes in mediating certain aspects of the disease process in preclinical studies. Several challenges remain regarding the development of protease inhibitors, including the synthesis of highly potent and specific inhibitors, and target validation in man.