Privat-docent thesis
Open access

Identification of pharmacological inhibitors of NADPH oxidases for the treatment of oxidative stress-derived pathologies

ContributorsJaquet, Vincent
Defense date2021-11-01

Excessive oxidant generation leads to tissue damage through modification of biological macromolecules, cellular membranes and extracellular matrix. This situation of oxidative stress is a key pathological feature of numerous diseases, such as cardiovascular, neurological and fibrotic diseases. Although the sources of oxidants in cells are variable, the family of NADPH oxidases (NOX) has as sole known function to generate reactive oxygen species (ROS). There are seven NOX with various tissue expression. As professional ROS generators in specific tissues, NOX represent pharmacological targets of great interest. The main objective of the research compiled in this thesis was to study the feasibility and therapeutic potential of NOX inhibition. Two studies represent proof of principle studies using NOX-deficient mice to address the roles of several NOX isoforms in cardiovascular disease (myocardial infarction) and neurodegenerative disease (amyotrophic lateral sclerosis). Three other studies focus on the discovery, characterization and validation of novel bioavailable small molecule NOX inhibitors. We identified that NOX1 and NOX2 are important contributors of myocardial damage during the reperfusion phase following myocardial ischemia while NOX4 is not. We also showed that genetic deletion of or pharmacological inhibition of specific NOX isoforms present in the central nervous system did not improve survival or motor function in a mouse model of amyotrophic lateral sclerosis. To support the discovery of novel specific and selective NOX inhibitors, we developed a flowchart of assays to identify and validate a bona fide NOX inhibitor. Application of this validation pipeline elucidated that most of the widely reported NOX inhibitors have a multitarget mode of action and/or interfere with the readouts and are not specific for NOX. Using this approach, we validated the family of N-substituted phenothiazines as general NOX inhibitors as well as a potent and bioavailable compound GSK2795039 specific for the NOX2 isoform. The established screening and validation flowchart will allow identification of novel highly specific NOX inhibitors to enable further validation of NOX as potential drug targets.

Citation (ISO format)
JAQUET, Vincent. Identification of pharmacological inhibitors of NADPH oxidases for the treatment of oxidative stress-derived pathologies. 2021. doi: 10.13097/archive-ouverte/unige:156983
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Creation11/23/2021 10:10:00 AM
First validation11/23/2021 10:10:00 AM
Update time03/16/2023 2:00:59 AM
Status update03/16/2023 2:00:59 AM
Last indexation08/31/2023 7:06:54 AM
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