Keap1-targeting protein-like polymers show long circulation and Nrf2 activation in mice
- Keap1-inhibiting protein-like polymers block the Keap1/Nrf2 protein-protein interaction to boost antioxidant defense, a strategy relevant to neurodegeneration and myocardial infarction.
- Mouse PK/PD at three doses showed very long circulation times and large distribution volumes, concentrated in clearance organs.
- In Nrf2 reporter mice, pathway activation was strong in liver and kidney, and was also seen in striatum and hippocampus.
💡 Points
Long half-life plus a large volume of distribution raises a basic question: is this Keap1 PPI blocker engaging its target, or simply parked in liver and kidney? Reporter signal in striatum and hippocampus is encouraging, yet free brain exposure and chronic-dosing tolerability are unknown, and sustained Nrf2 activation is not benign.