Indole-based Inhibitors of Neutrophil Myeloperoxidase: Potential Therapeutics for the Treatment of Cystic Fibrosis

Cystic Fibrosis (CF) is a hereditary disease resulting in the accumulation of viscous mucus in the lung. CF patients suffer chronic infections and overwhelming inflammation that leads to pulmonary dysfunction and ultimately premature death. Chronic inflammation in the CF lung is associated with exuberant neutrophilic infiltration of the CF airway. Neutrophils abundantly express the proinflammatory enzyme myeloperoxidase (MPO) that can cause oxidative injury to the CF airway. Therefore, we have hypothesized that MPO is an important therapeutic target for the treatment of CF. Previous studies in our lab have identified indole-based compounds as inhibitors of MPO. A survey of natural products possessing an indole moiety has revealed plant-based compounds (‘auxins’) as inhibitors of MPO. Accordingly, we tested a series of natural and synthetic indole-based derivatives as MPO inhibitors. Using a spectrophotometric assay to assess MPO activity, we have established that natural and synthetic indole compounds are inhibitors of MPO. Some of these compounds are extremely potent inhibitors of MPO (IC₅₀ ~30 nM), while others are essentially inactive (IC₅₀ values > than 100 µM). These observations were further validated using a second assay that quantifies hydrogen peroxide consumption by MPO. Indoles substituted with alkyl alcohols are superior to those harboring carboxylic acids or those with extensive conjugation, revealing important structure-activity relationships (SAR). Our studies provide the framework for the development of potent and selective MPO inhibitors, and define the potential utility of these indole-based compounds as therapeutic agents to ameliorate oxidative stress associated with CF and other inflammatory diseases.