Finding inhibitors of myeloperoxidase – towards suppressing neutrophilic damage in inflammatory diseases.
Our immune system relies on white blood cells called neutrophils to protect us from bacterial infections. Neutrophils ingest bacteria and kill them in intracellular compartments, using the enzyme myeloperoxidase to generate an oxidative assault. Unfortunately, in many inflammatory diseases myeloperoxidase leaks out of neutrophils and indiscriminately damages healthy tissue through the production of chlorine bleach, or indirectly via activation of proteases, such as elastase. Inhibitors of extracellular myeloperoxidase would be beneficial for patients with atherosclerosis, rheumatoid arthritis, cystic fibrosis and other respiratory complications such as pneumonia in COVID-19 sufferers. They would act by blocking the production of bleach, thereby preventing inflammatory tissue damage. Currently there are no drugs that specifically target myeloperoxidase. We have studied myeloperoxidase for 30 years, including collaborations with the pharmaceutical industry. Previous CMRF funding helped us develop a screening assay for potential drugs that target the enzyme. Using this assay, we have now identified a new class of candidate molecules that are potent inhibitors of myeloperoxidase. Initial data indicates that these compounds act differently from known inhibitors, and will shed light on how myeloperoxidase is most effectively inhibited. In this project, we will determine the potency, selectivity, and molecular mechanisms of these new inhibitors. This information will help drive the development of pharmacological inhibitors for treating several human inflammatory diseases.