University of Pittsburgh researchers have invented the first specific peptide inhibitor of NADPH Oxidase 1 (Nox1), an enzyme in mammalian cells responsible for the production of reactive oxygen species (ROS) including superoxide (O2·-) and/or hydrogen peroxide (H2O2).
Description
Various forms of Nox enzymes exist (isoforms) and are involved in regulating ROS levels in cells dependent on the cell requirements. However, excessive ROS production has been linked to hypertension and a host of other health conditions including metastasis of colon carcinomas. Selective inhibition of Nox1 may be a novel approach to treat dysregulation and excess ROS production.
Applications
1. Cardiovascular disease
2. Cancer
3. Neurological disorders
4. Other conditions involving ROS
Advantages
This novel protein is the first specific peptide inhibitor of Nox1. Based on the native peptide used to regulate Nox1 activation, this novel peptide has been mutated and inhibits the enzyme activity of Nox1. This peptide selectively inhibits Nox1 activity with lower risk of side effects and toxicity when used in vivo.
Invention Readiness
The activation of Nox1 is regulated by specific cytosolic proteins, including NOXA1. Through design, a peptide mimicking a small portion of NOXA1 was modified to produce a peptide containing 11 amino acids called NoxA1ds. This peptide, [NH3]-EPVDALGKAKV-[CONH2] selectively binds to Nox1 and inhibits the enzyme function of Nox1 with an IC50 of 5.1nM. Studies using NoxA1ds in concentrations up to 10mM have shown no inhibition of Nox2 or Xanathine Oxidase confirming the selective nature of this inhibitor. A peptide, NoxA1ds, has been synthesized and in vitro studies have demonstrated selective inhibition of Nox1 isoforms. Further optimization of compound may improve efficacy.
IP Status
https://patents.google.com/patent/US9770481B2