SAFit-ligands provide the foundation for a mechanistically novel treatment of stress-related psychiatric disorders
The FK506-binding protein 51 (FKBP51) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the very similar functional counterplayer FKBP52. Scientists at the Max Planck Institute of Psychiatry in Munich have now developed the first potent and highly selective inhibitor of FKBP51. The so-called SAFit-ligand inhibits FKBP51 enhancing growth of neuronal cell cultures and improving stress-coping behavior in mice. These findings provide the structural and functional basis for the development of mechanistically novel antidepressants.
The SAFit-ligand (blue/green) is a highly selective inhibitor of FKBP51 (grey), a risk factor for stress-related psychiatric disorders. The binding of SAFit induces a conformational change (red protein side chain) in FKBP51, but not in its very similar functional counterplayer FKBP52.
Credit: © MPI of Psychiatry / Felix Hausch