Washington State University

Pacific Northwest Biotechnology Inc.

John W Wright

Joseph W Harding

Leen H Kawas

Caroline C Benoist

Gary A Wayman

Patrick D Elias

Brent J Yamamoto

Small molecule, peptidic hepatocyte growth factors mimics, which act as both mimetics and antagonists, have been generated. These molecules have been shown or predicted to have therapeutic potential for numerous pathologies including dementia, neurodegenerative disease, diabetes and metabolic syndrome, cancer, and defective wound healing.

Hepatocyte growth factor mimics as therapeutic agents

Angiotensin-like factor compositions and methods for using them to diagnose, prevent and/or treat conditions associated with c-Met dysregulation, are provided. The conditions include cancer, obesity, conditions associated with obesity, and neurodegenerative diseases such as general dementia, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, traumatic brain injury and spinal cord trauma.

C-Met receptor regulation by angiotensin IV (AT4) receptor ligands

Small molecule, peptidic hepatocyte growth factors mimics, which act as both mimetics and antagonists, have been generated. These molecules have been shown or predicted to have therapeutic potential for numerous pathologies including dementia (e.g. Alzheimer's) and Parkinson's disease.

The cell surface c-Met receptor, through which hepatocyte growth factor (HGF) signals are mediated, has now been identified as the Angiotensin-IV receptor (AT(4)R) in processes that include HGF-regulated cell motility, angiogenesis, cancer metastasis, adipogenesis and others. Disclosed are angiotensin-like factor compositions and methods for using them to diagnose, prevent and/or treat conditions associated with c-Met dysregulation, including cancer, obesity and conditions associated with obesity, and other disorders, for example, by altering hepatocyte growth factor activity or c-Met receptor activity by administering an angiotensin-like factor that specifically binds to a cell surface c-Met receptor.

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The cell surface c-Met receptor, through which hepatocyte growth factor (HGF) signals are mediated, has now been identified as the Angiotensin-IV receptor (AT(4)R) in processes that include HGF-regulated cell motility, angiogenesis cancer metastasis and others. Disclosed are angiotensin-like factor compositions and methods for using them to diagnose, prevent and/or treat conditions associated with c-Met dysregulation, including altering hepatocyte growth factor activity or c-Met receptor activity by administering an angiotensin-like factor that specifically binds to a cell surface c-Met receptor.

ATreceptor agonists are potent activators of angiogenesis and can be used to treat diseases that are characterized by vascular insufficiency. ATreceptor antagonists, which are potent inhibitors of angiogenesis, and can be used as anti-angiogenic agents for the treatment of cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerotic plaque formation, and any disease process that is characterized by excessive, undesired or inappropriate angiogenesis or proliferation of endothelial cells.

AT4 receptor ligands as angiogenic, anti-angiogenic, and anti-tumor agents

A unique and novel angiotensin AT4 receptor and AIV ligand system for binding a small N-terminal hexapeptide fragment of Angiotensin II (referred to as AIV, with amino acid sequence Val.sub.1 -Tyr.sub.2 -Ile.sub.3 -His.sub.4 -Pro.sub.5 -Phe.sub.6 ; SEQ. ID. NO. 1) is disclosed. AIV ligand binds saturably, reversibly, specifically, and with high affinity to membrane AT4 receptors in a variety of tissues, including heart, lung, kidney, aorta, brain, liver, and uterus, from many animal species. The AT4 receptor is pharmacologically distinct from classic angiotensin receptors (AT1 or AT2). The system employs AIV or C-terminally truncated or extended AIV-like peptides (e.g., VYIHPFX; SEQ. ID. NO. 8) as the signaling agent, and the AT4 plasma membrane receptor as the detection mechanism. The angiotensin AT4 receptor and receptor fragments (including the receptor binding site domain) are capable of binding a VYIHPF (SEQ. ID. NO. 1) angiotensin AIV N-terminal peptide but not an angiotensin AII or AIII N-terminal peptide, i.e., DRVYIHPF (SEQ. ID. NO. 2) or RVYIHPF (SEQ. ID. NO. 3), respectively. Also disclosed are processes for isolating angiotensin AT4 receptor and AIV angioteninase, identifying angiotensin AIV agonists and antagonists, and constructing diagnostic assays to specifically measure AIV and AI-specific angiotensinase in biological fluids.

Growing community of inventors

Pullman, WA, United States of America

John W Wright