Abstract
FOXO4-DRI (FOXO4-D-retro-inverso) is a cell-permeable peptide designed to disrupt the interaction between forkhead box O4 (FOXO4) and p53 in senescent cells. The peptide uses D-amino acids in a retro-inverso configuration for enhanced protease resistance while maintaining binding function.
Molecular Background
- Structure: 46 amino acids, all D-amino acids, retro-inverso configuration
- Half-life: Over 48 hours in plasma due to protease resistance
- Binding affinity: Kd approximately 0.3 µM for FOXO4
- Cell penetration: Via arginine-rich motif
Proposed Mechanism
In senescent cells, the FOXO4-p53 interaction becomes stabilized, which prevents p53-mediated apoptosis. FOXO4-DRI is designed to:
- Competitively displace p53 from FOXO4 binding
- Restore nuclear p53 localization in senescent cells
- Enable p53-dependent apoptosis pathways
- Selectively affect senescent cells with the stabilized complex
Research Applications
- Cellular Senescence Studies: Investigating senescent cell clearance mechanisms
- Aging Research: Models of accelerated and natural aging
- SASP Research: Senescence-associated secretory phenotype modulation
- Protein-Protein Interaction: Studies of FOXO4-p53 complex disruption
Preclinical Research
Published studies have examined FOXO4-DRI in:
- Progeroid mouse models
- Naturally aged rodent models
- Chemotherapy-induced senescence models
- In vitro senescent fibroblast cultures
Selectivity
Research indicates specificity for senescent cells with the stabilized FOXO4-p53 complex. Studies report minimal effects on proliferating or quiescent cells lacking this interaction.
Current Research Status
As of December 2025, FOXO4-DRI remains in preclinical research. No human trials have been initiated. The evidence base comes primarily from the originating research laboratories, and independent replication is an area for future investigation.