Indole-based Inhibitors of Leukocyte-derived Myeloperoxidase as Potential Novel Therapeutics for the Treatment of Inflammatory Diseases

It is now well appreciated that many cardiovascular and respiratory diseases are accompanied by robust inflammation and tissue injury. Neutrophils are a prevalent cell facilitating inflammatory tissue injury. Neutrophils induce tissue injury during inflammation by promoting oxidative stress.  It is this oxidative stress that is thought to alter the structure and function of cells.  Myeloperoxidase (MPO) is a highly abundant hemoprotein expressed by neutrophils that catalyzes the formation of hypochlorous acid (HOCl, or ‘bleach’) by hydrogen peroxide (H₂O₂)-dependent oxidation of chloride (Cl^-).  Because of its high reactivity, HOCl can chlorinate and oxidize many important biological molecules and is thought to provide a mechanism accounting for cellular injury during inflammation.  Based upon these premises, we hypothesized that MPO is a particularly attractive therapeutic target for treating inflammatory diseases. The goal of our study was to identify small molecules with the capacity to potently inhibit MPO.  Preliminary data in our laboratory have indicated that indole-based molecules can inhibit MPO.  Taking this into account, both natural indoles and synthetic analogs were tested for efficacy to inhibit MPO. The potency of candidate compounds was examined using spectrophotometric and electrode-based assays.   Preliminary data reveal that some of the indole derivatives are highly potent inhibitors of MPO (ie. nM potency).  Additionally, structure-activity relationships were revealed and provide a framework for the rationale design of even more potent indole-based inhibitors of MPO.  Our data reveal that indole-based small molecules may be particularly useful as anti-inflammatory agents for the treatment of many cardiovascular and respiratory diseases.