Crystal-guided macrocycles hit KEAP1–NRF2 to ease depression-like behavior in mice
- Guided by KEAP1 crystal structures, the team built non-peptide macrocycles that block its contact with NRF2, a notoriously hard protein–protein interface.
- Lead compound T7 binds fast and dissociates slowly, curbs oxidative stress and inflammation in cells, and reaches the brain.
- In stressed mice it eased depression-like behavior and neurotransmitter changes via NRF2 activation, and limited copper-linked cuproptosis damage in the hippocampus and cortex.
💡 Points Based on the abstract
Fast-on, slow-off is the number to chase: for a PPI like this, residence time often matters more than Kd. Brain penetration from a non-peptide macrocycle is the surprise, so brain/plasma ratio, free fraction, and off-target selectivity are the next asks. And how many steps is T7? If the macrocyclization is clunky, SAR expansion stalls.