Selective inhibitors of the FK506-binding protein 51 by induced fit

• Published in: Nature chemical biology Vol. 11; no. 1; pp. 33 - 37
• Main Authors: Gaali, Steffen, Kirschner, Alexander, Cuboni, Serena, Hartmann, Jakob, Kozany, Christian, Balsevich, Georgia, Namendorf, Christian, Fernandez-Vizarra, Paula, Sippel, Claudia, Zannas, Anthony S, Draenert, Rika, Binder, Elisabeth B, Almeida, Osborne F X, Rühter, Gerd, Uhr, Manfred, Schmidt, Mathias V, Touma, Chadi, Bracher, Andreas, Hausch, Felix
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2015; Nature Publishing Group
• Subjects: 631/154/309/2420; 631/154/556; 631/92/436; 631/92/96; Adaptation, Psychological - drug effects; Animals; Antidepressants; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Binding Sites - drug effects; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Cells, Cultured; Chemistry; Chemistry/Food Science; Drug Discovery; Humans; Inhibitors; Ligands; Male; Mental depression; Mental disorders; Mice; Mice, Inbred C57BL; Mutation - genetics; Neurites - drug effects; Protein Conformation; Proteins; Psychopharmacology; Risk factors; Tacrolimus Binding Proteins - antagonists & inhibitors; Tacrolimus Binding Proteins - chemistry; Tacrolimus Binding Proteins - drug effects
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1699

Inhibitors of FKBP51 with antidepressive activity are selective over the related FKBP52 and bind FKBP51 by an induced-fit mechanism that causes a conformational change. The analogous conformational change in FKBP52 generates a strained conformation. 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.