Felix Hausch1. 1. Max Planck Institute of Psychiatry, 80804 Munich, Germany. Electronic address: hausch@mpipsykl.mpg.de.
Abstract
BACKGROUND: Ligands for FK506-binding proteins, also referred to as neuroimmunophilin ligands, have repeatedly been described as neuritotrophic, neuroprotective or neuroregenerative agents. However, the precise molecular mechanism of action underlying the observed effects has remained elusive, which eventually led to a reduced interest in FKBP ligand development. SCOPE OF REVIEW: A survey is presented on the pharmacology of neuroimmunophilin ligands, of the current understanding of individual FKBP homologs in neuronal processes and an assessment of their potential as drug targets for CNS disorders. MAJOR CONCLUSIONS: FKBP51 is the major target accounting for the neuritotrophic effect of neuroimmunophilin ligands. Selectivity against the homolog FKBP52 is essential for optimal neuritotrophic efficacy. GENERAL SIGNIFICANCE: Selectivity within the FKBP family, in particular selective inhibition of FKBP12 or FKBP51, is possible. FKBP51 is a pharmacologically tractable target for stress-related disorders. The role of FKBPs in neurodegeneration remains to be clarified. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
BACKGROUND: Ligands for FK506-binding proteins, also referred to as neuroimmunophilin ligands, have repeatedly been described as neuritotrophic, neuroprotective or neuroregenerative agents. However, the precise molecular mechanism of action underlying the observed effects has remained elusive, which eventually led to a reduced interest in FKBP ligand development. SCOPE OF REVIEW: A survey is presented on the pharmacology of neuroimmunophilin ligands, of the current understanding of individual FKBP homologs in neuronal processes and an assessment of their potential as drug targets for CNS disorders. MAJOR CONCLUSIONS: FKBP51 is the major target accounting for the neuritotrophic effect of neuroimmunophilin ligands. Selectivity against the homolog FKBP52 is essential for optimal neuritotrophic efficacy. GENERAL SIGNIFICANCE: Selectivity within the FKBP family, in particular selective inhibition of FKBP12 or FKBP51, is possible. FKBP51 is a pharmacologically tractable target for stress-related disorders. The role of FKBPs in neurodegeneration remains to be clarified. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
Authors: Marine Bacchi; Magali Jullian; Serena Sirigu; Benjamin Fould; Tiphaine Huet; Lisa Bruyand; Mathias Antoine; Laurent Vuillard; Luisa Ronga; Leonard M G Chavas; Olivier Nosjean; Gilles Ferry; Karine Puget; Jean A Boutin Journal: Protein Sci Date: 2016-10-13 Impact factor: 6.725
Authors: David Dilworth; Geoff Gudavicius; Xiaoxue Xu; Andrew K J Boyce; Connor O'Sullivan; Jason J Serpa; Misha Bilenky; Evgeniy V Petrochenko; Christoph H Borchers; Martin Hirst; Leigh Anne Swayne; Perry Howard; Christopher J Nelson Journal: Nucleic Acids Res Date: 2018-03-16 Impact factor: 16.971