First-in-class Nox inhibitor and development of other isoform-selective Nox inhibitors
The understanding of the specific role of each Nox isoform in a signaling pathway or pathophysiological process has been hindered by the paucity of specific Nox inhibitors. A major focus of our research has been the development of isoform-specific inhibitors, both peptidic as well as small molecules. Nox2ds-tat, was the first Nox inhibitor rationally designed to specifically inhibit Nox2- oxidase activity (2a, 2b) and to date is arguably the most widely used not only in the cardiovascular field but also in the study of numerous diseases where Nox2-derived ROS are involved, including neurodegenerative disease and cancer. Nox2ds-tat is a peptidic inhibitor designed to mimic the docking sequence on Nox2 that is important for its interaction with p47phox and that contains a short amino acid region corresponding to HIV-tat protein, this provides our inhibitor with the capacity to cross plasma membrane and block subunit assembly and thus superoxide generation. A related yet distinct strategy was used to develop a Nox1-specific inhibitor (2c). In this case, the peptide NoxA1ds blocks the interaction of Nox1 with NoxA1 necessary for superoxide anion production. In the case of small molecule inhibitors, we have identified two compounds that specifically inhibit Nox2, using high throughput screening, rational design and stringent biochemical assays (2d).
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