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Free keywords:
AFFECTIVE-DISORDERS, TREATMENT RESPONSE, FKBP52, STRESS, IMMUNOPHILIN,
MICE, LIGANDS, FK506, COCHAPERONE, PHYSIOLOGYBiochemistry & Molecular Biology; Biophysics;
Abstract:
The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) 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 structurally
similar but functional opposing homolog FKBP52, and all known FKBP
ligands are unselective. Here, we report the discovery of the potent and
highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class
of ligands achieves selectivity for FKBP51 by an induced-fit mechanism
that is much less favorable for FKBP52. By using these ligands, we
demonstrate that selective inhibition of FKBP51 enhances neurite
elongation in neuronal cultures and improves neuroendocrine feedback and
stress-coping behavior in mice. Our findings provide the structural and
functional basis for the development of mechanistically new
antidepressants.
