摘要
This mini-review presents the authors＇ vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 （Nrf2）, and in particular, via disruption of Nrf2-Keap 1 interaction. There are two opposite ＂chemical＂ mechanisms underlying such activation： the first one is a non-specific covalent modification of Keapl thiols, resulting in side effects of varied severity, and the second one is the shift of the Nrf2-Kelch-like ECH associated protein-1 （Keapl） binding equilibrium in the presence of a competitive and chemically benign displacement agent. At this point, no displacement activators exhibit sufficient biological activity in comparison with common Nrf2 activators working via Keapl thiol modification. Hence, the hope in therapeutics is now linked to the FDA approved dimethylfumarate, whose derivative, monomethylfumarate, as we demonstrated recently, is much less toxic but equally biologically potent and an ideal candidate for clinical trials right now. A newly emerging player is a nuclear inhibitor of Nrf2, BTB domain and CNC homolog 1 （Bach1）. The commercially developed Bachl inhibitors are currently under investigation in our laboratory showing promising results. In our viewpoint, the perfect future drug will present the combination of a displacement activator and Bach 1 inhibitor to insure safety and efficiency of Nrf2 activation.
This mini-review presents the authors＇ vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 （Nrf2）, and in particular, via disruption of Nrf2-Keap 1 interaction. There are two opposite ＂chemical＂ mechanisms underlying such activation： the first one is a non-specific covalent modification of Keapl thiols, resulting in side effects of varied severity, and the second one is the shift of the Nrf2-Kelch-like ECH associated protein-1 （Keapl） binding equilibrium in the presence of a competitive and chemically benign displacement agent. At this point, no displacement activators exhibit sufficient biological activity in comparison with common Nrf2 activators working via Keapl thiol modification. Hence, the hope in therapeutics is now linked to the FDA approved dimethylfumarate, whose derivative, monomethylfumarate, as we demonstrated recently, is much less toxic but equally biologically potent and an ideal candidate for clinical trials right now. A newly emerging player is a nuclear inhibitor of Nrf2, BTB domain and CNC homolog 1 （Bach1）. The commercially developed Bachl inhibitors are currently under investigation in our laboratory showing promising results. In our viewpoint, the perfect future drug will present the combination of a displacement activator and Bach 1 inhibitor to insure safety and efficiency of Nrf2 activation.
基金
supported in part by grants from NIH NS062165,NS060885,Michael J Fox Foundation for Parkinson’s Research
Parfore Parkinson,National Parkinson Foundation(CSRA chapter) to BT
Winifred Masterson Burke Foundation
Thomas Hartman Foundat ion for Parkinson’s disease to IGG
