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.
Public Health Relevance Statement: PROJECT NARRATIVE 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.
NIH Spending Category: Aging; Atherosclerosis; Cardiovascular
Project Terms: 3-chlorotyrosine; 3-mononitrotyrosine; 3-nitrotyrosine; Acute; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Arterial Fatty Streak; Assay; Astrocytes; Astrocytus; Astroglia; Atheroma; Atheromatous; Atheromatous degeneration; Atheromatous plaque; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; Bioassay; Bioavailable; Biologic Assays; Biological Assay; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Blood Segmented Neutrophil; Blood leukocyte; Cell Function; Cell Process; Cell physiology; Cellular Assay; Cellular Function; Cellular Physiology; Cellular Process; Characteristics; Chloride; Chloride Ion; Chlorides; Cholest-5-en-3-ol (3beta)-; Cholesterol; Chronic; Chronic Disease; Chronic Illness; Cl- element; Clinic; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Development; Disease; Disorder; Enzymes; Generations; H2O2; HDL; Heavy Lipoproteins; Heterophil Granulocyte; High Density Lipoproteins; High density lipoprotein; Human; Human, General; Hydrogen Peroxide; Hydrogen Peroxide (H2O2); Hydroperoxide; Hypochlorous Acid; Impairment; In Vitro; Infection; Inflammatory; Ischemia; L-lysine, N(6)-(aminocarbonyl)-; LDL oxidation; Lead; Lesion; Leukocytes; Link; Lipids; Lipoprotein LDL Receptors; Lipoproteins; Lipoproteins, HDL; Low Density Lipoprotein Receptor; Low Density Lipoprotein oxidation; Mammals, Mice; Man (Taxonomy); Man, Modern; Marketing; Marrow Neutrophil; Marrow leukocyte; Mice; Murine; Mus; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Normal Tissue; Normal tissue morphology; Oxidants; Oxidizing Agents; Pb element; Peroxidases; Phase; Polymorph; Polymorphonuclear Cell; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; Primary Senile Degenerative Dementia; Proteins; Reaction; Receptors, LDL; Reperfusion Therapy; Research; Reticuloendothelial System, Leukocytes; SBIR; SBIRS (R43/44); Screening procedure; Series; Severities; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Staging; Streaks, Arterial Fatty; Subcellular Process; Testing; Therapeutic; Therapeutic Agents; Transgenic Mice; White Blood Cells; White Cell; alpha-Lipoproteins; atheromatosis; atherosclerosis plaque; atherosclerotic lesions; atherosclerotic plaque; atherosclerotic vascular disease; chlorination; chronic disease/disorder; chronic disorder; dementia of the Alzheimer type; design; designing; disease/disorder; electron acceptor; enzyme activity; experiment; experimental research; experimental study; gene product; heavy metal Pb; heavy metal lead; homocitrulline; improved; in vivo; in vivo Model; inhibitor; inhibitor/antagonist; macrophage; mouse model; neutrophil; new therapeutics; next generation therapeutics; nitrotyrosine; novel; novel therapeutics; oxidation; peroxidation; primary degenerative dementia; public health relevance; reperfusion; research study; reverse cholesterol transport; screening; screenings; senile dementia of the Alzheimer type; small molecule; small molecule libraries; ureidocaproic acid; vulnerable plaque; white blood cell; white blood corpuscle
