Development of myeloperoxidase inhibitors to treat atherosclerosis

Maki, Richard

Abstract

The overall objective of the proposed research is to develop an orally active inhibitor of MPO as a treatment for acute and chronic diseases. MPO is an abundant enzyme in leukocytes and its expression can be induced in macrophages at inflammatory sites such as atherosclerotic lesions. MPO catalyzes a reaction between chloride and hydrogen peroxide to generate hypochlorous acid, a strong oxidizing agent. Multiple lines of evidence implicate MPO in the initiation and progression of atherosclerosis through oxidation of lipoproteins, impairment of reverse cholesterol transport, and reduction of bioavailable NO. A small molecule inhibitor of MPO may be an important component in a list of therapeutic options for the treatment of chronic inflammatory diseases including atherosclerosis.
In Specific Aim 1 we propose to screen a small molecule library for inhibitors of MPO.
In Specific Aim 2 we propose to test the small molecule inhibitors in a variety of secondary assays designed for selectivity and cellular function before testing the small molecule in an in vivo model of atherosclerosis.

Public Health Relevance

Myeloperoxidase is recognized as an important causative contributory agent in inflammatory diseases including atherosclerosis. An inhibitor of myeloperoxidase would provide a novel therapeutic agent that could be used as an adjunct therapy to statins and other therapeutics already on the market. The experiments outlined in this Phase I SBIR application will help set the stage for the development of a novel and safe myeloperoxidase inhibitor.