Therapeutic Targeting of Myeloperoxidase in Acute Vascular Inflammation. Polymorphonuclear neutrophils (PMNs) are recognized as critical mediators of vascular injury during acute episodes of inflammation such as sepsis and acute coronary syndromes. Myeloperoxidase (MPO), a hemoprotein abundantly expressed by PMNs and secreted during activation, possesses potent proinflammatory properties and may contribute directly to tissue injury. In addition to serving as a catalytic `sink'for nitric oxide (NO), MPO also catalyzes oxidation, nitration, and chlorination reactions known to modulate physiological and pathological events during inflammatory responses. Additionally, recent studies have demonstrated that MPO serum levels powerfully predict an increased risk for subsequent cardiovascular events and extend the prognostic information gained from traditional biochemical markers. Moreover, a growing body of evidence now supports a causal role of MPO in compromised vascular NO signaling in humans, and this notion is largely confirmed in MPO knock-out mice. Biochemical, cellular, and physiological data support the notion that therapeutic inhibition of MPO would be beneficial for mitigating the injurious effects of this enzyme during acute inflammatory episodes. Currently, however, there are no biologically compatible strategies available to scientists and clinicians for therapeutic inhibition of the catalytic activities of MPO. Therefore, small-molecule inhibitors of MPO could prove useful in the treatment of acute inflammatory vascular diseases. Whereas inhibitors of MPO have been previously identified, most either possess inherent toxicity, nonselective biological effects, or are not of sufficient potency to be utilized as effective therapeutics in vivo. We have recently discovered that substituted phenylthiourea (PTU) derivatives are potent inhibitors of MPO in vitro. Based upon above premises, and our preliminary data, Based upon these premises, and our preliminary data, we hypothesize that substituted thioureas can serve as anti- inflammatory and vasoprotective agents during acute inflammation by inhibiting the catalytic reactions of MPO. To test this hypothesis, the following specific aims will be addressed: 1) To construct a rationally- designed series of thiourea-based inhibitors of MPO, and elucidate structure/activity relationships with the intention of designing powerful inhibitors with physical properties and toxicity profiles amenable to therapeutic use, and 2) To define the capacity of thiourea-based MPO inhibitors to serve as anti-inflammatory and vasoprotective agents, and to utilize these inhibitors to elucidate the mechanisms by which MPO contributes to systemic injury during acute episodes of inflammation using physiological, genomic and metabolomic approaches. Successful completion of these studies will provide, for the first time, small molecule therapeutics that target MPO for the treatment of acute vascular inflammation and injury. Additionally, the development and use of these novel inhibitors will expand the repertoire of animal models that can be utilized (where gene knockouts are not available) to further define the mechanisms by which MPO induces vascular injury during inflammation and assess the extent to which this can be modulated pharmacologically.
Project Narrative: Neutrophils play important contributing roles to vascular injury during acute episodes of inflammation such as that which occurs during sepsis and myocardial infarction. Myeloperoxidase (MPO) is a highly abundant hemoprotein/enzyme expressed by neutrophils that produces reactive species that can both damage the blood vessel wall and compromise vascular nitric oxide signaling and physiology. Despite this knowledge, no therapeutic strategies to inhibit MPO are currently available. We anticipate that our studies will lead to the development of novel small molecule inhibitors of MPO that could potentially be utilized as therapeutics for the treatment of acute vascular inflammatory diseases, and will allow for further elucidation of the mechanisms by which MPO induces vascular injury during inflammation.
