FK506-binding proteins have been implicated in numerous human diseases suggesting
novel therapeutic opportunities. In particular, the large FKBP51 has emerged as an important regulator
of the stress-coping system and as an established risk factor for stress-related disorders. The principal
druggabilty of FKBPs is evidenced by the prototypical high affinity ligands FK506 and rapamycin but
the development of more refined and selective chemical probes for FKBPs has been challenging. In
this review we summarize recent advances in the development of FKBP ligands, which cumulated in
the first highly selective ligands for FKBP51. The best ligand SAFit2 allowed the proof-of-concept in
mice for FKBP51 inhibitors as potentially novel antidepressants. Finally, we discuss pending issues that need to be addressed
for the further development of FKBP51-directed drugs.
Keywords: Antidepressants, FKBP ligand, FKBP51-directed drugs, FK506-binding proteins, homology, therapeutic.
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