Development of an Endothelial Nitric Oxide Synthase Mutant Resistant to Inhibition by Oxidative Stress for the Treatment of Endothelial Dysfunction

Description:

Current State of the Art:

A major complication of vascular disease is endothelial dysfunction caused by oxidative stress to the vasculature.  Treatment options include surgery, implantation of stints, medications and lifestyle changes.  Currently there are no gene therapy treatments available for endothelial dysfunction.  Available chemical and pharmaceutical treatments do not work on a cellular level, though research is underway to study the molecular biology of this mechanism. The biochemistry of cellular oxidative stress links nitric oxide (NO) to endothelial function, which is why various existing treatment regimens and studies target eNOS modulation to improve vascular function.

 

Problems with the Current Art:

Endothelial production of NO is critical to the regulation of vascular responses.  When bioavailable vascular NO is deficient, endothelial dysfunction results, causing development of atherosclerosis, thrombosis, inflammation, vasoconstriction.  The problem with the current art, however, is determining how best to modulate eNOS for the purpose of managing oxidative stress to and damage of the vasculature.

 

Advantages of the Novel Invention:

The invention is an endothelial nitric oxide synthase (eNOS) mutant that is resistant to inhibition by oxidative stress.  It is an  enzyme that has been modified in the ZN tetrathiolate cluster to provide oxidant insensitivity and to produce NO under oxidative stress in endothelial cells.  This mutant synthase features a redox stable functional enzyme which greatly reduces oxidation and eNOS dimer disruption, allowing for increased production of NO under oxidative stress.  Replacement of the ZnS4 cluster provides oxidant insensitivity.  Enriching the arginine constituents stabilizes the structure,  Enabling NO production improves patient outcomes by allowing for improved regulation of and enhanced vascular function, thereby diminishing endothelial dysfunction.

Case ID:  GRU #2011-023

Patent Information:
Category(s):
Therapeutics
For Information, Contact:
AU
Unassigned
Augusta University
mta@augusta.edu
Inventors:
Stephen Black
Ruslan Rafikov
Keywords:
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