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Novel Peroxidase Inhibitors for Treatment of Chronic Inflammation

MCW #1595

 

 Key Inventors

Kirkwood A. Pritchard, PhD & Hao Zhang, PhD

 Background

Myeloperoxidase (MPO), a heme-containing protein, has long been recognized as an important mediator of vascular inflammation and cardiovascular disease. MPO is activated by hydrogen peroxide which enters the active site and removes two electrons. When chlorine enters the active site it is converted to hypochlorous acid. Similarly when tyrosine enters the active site it is converted to a tyrosine radical. Since they are both cytotoxic, hypochlorous acid and tyrosine radicals allow neutrophils and mononuclear cells to kill bacteria and other pathogens. In vascular systems, MPO is released from leukocytes and can modify HDL, induce LDL lipid peroxidation, and scavenge nitric oxide. During chronic states of inflammation such as diabetes, atherosclerosis, hypertension, sickle cell disease and asthma, white blood cells become activated and release a variety of peroxidases into vascular tissues. As all cells generate hydrogen peroxide, this free peroxidase creates an environment where secondary free radicals are produced on an ongoing basis. Under these conditions the vasculature is subjected to increased states of oxidative stress and inflammation. As chronic states of oxidative stress and inflammation are known to induce vascular disease and accelerate autoimmunity it becomes essential to inhibit aberrant peroxidase activity.

 Description

Researchers at the Medical College of Wisconsin have developed novel, non-toxic MPO inhibitors that could be effective therapeutic agents for treating vascular disease. These compounds inhibit peroxidase, scavenge peroxides and in the presence of normal healthy tissue appear to be self-regenerating. The inhibitors are a family of peptides comprised of 3 amino acid (AA) in which the first AA can be any of the 26 different amino acids in the number one position, a central nucleophil (tyrosine, tryptophan or an artificial amino acid melatonin) in the number two position and an adjacent cysteine in the third position. When the inhibitor enters the MPO active site, the enzyme extracts electrons from the central nucleophile rendering it inactive, thus preventing it from generating new free radicals until it is reactivated by another hydrogen peroxide. After the inhibitor leaves the active site of the peroxidase, it extracts a free electron (via hydrogen) from the free sulfhydryl group from the adjacent cysteine. The oxidized peptide is believed to be regenerated by free glutathione, possibly via glutathione directly or the glutathione peroxidase/ reductase pathway. When tested in vivo the tri-peptides were effective inhibitors of MPO-mediated LDL oxidation and improved vasodilatation and vascular function in murine models of chronic inflammation for sickle cell disease and chronic asthma.

 Features

• Unique, non-toxic compounds

• Simple, 3 amino acid peptide formulation with promising pharmacological properties

• Inhibits MPO-mediated HOCl formation at low concentrations

• Dose-dependently inhibits MPO-mediated protein nitration

• Broad-base therapeutic for a variety of chronic inflammatory conditions including asthma, atherosclerosis, sickle cell disease and ischemic heart disease

 Stage of Development

Pre-clinical data on asthma mouse model and sickle cell anemia mouse model

 Patents

Patent Pending.

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MEDICAL COLLEGE OF WISCONSIN
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Summary Information

Patent Status:
61/248,627

Disease Area:
Autoimmune/Inflammation
Pulmonary System

Mechanism of Action:
Inhibitor

Molecule Type:
Peptide

Patent Coverage Type:
Composition of Matter
Method of Use

Geographical Coverage:
Worldwide Patent

Related Areas of Interest:

Blood
Cardiovascular
Central Nervous System
Digestive System

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