Immunophilin ligands for the treatment of neurological disorders

Abstract

The immunophilins are members of a large, ubiquitous and highly conserved family of proteins known collectively as the peptidylprolyl cis-trans isomerases (PPIases). In addition to their enzymatic activity, certain PPIases have also been characterised as the cellular binding proteins for the immunosuppressant drugs FK506, rapamycin and cyclosporin A. Recently, it has been discovered that immunophilins are enriched 10- to 40-fold more in the brain than in the immune tissues, and that FK506 possesses neurotrophic properties in vitro and in vivo. Immunosuppressant drugs such as FK506 possess two distinct domains. One portion of FK506 binds to the immunophilin FKBP12; the remaining ‘effector domain’ of the immunosuppressant plays a critical role in interactions of the drug-immunophilin complex with the secondary protein target calcineurin. Inhibition of calcineurin’s phosphatase activity is responsible for the observed suppression of T-cell proliferation. It has been demonstrated that the neurotrophic effects of FK506 reside in the FKBP-binding domain. Small molecule mimetics of the FKBP-binding portion of FK506 retain the neurotrophic effects of the immunosuppressant, but lack immunosuppressant ability. These results provide a clear structural basis for the rational design of novel small molecules that possess neurotrophic actions, but are devoid of immunosuppressive activity. FKBP12 ligands potently promote neurite outgrowth in cultured sensory neurones at picomolar concentration. The in vivo efficacy of these compounds has been evaluated in several animal models of neurodegenerative disease. Immunophilin ligands have been found to promote structural and functional recovery following lesioning of a variety of neuronal populations in the central and peripheral nervous systems. As such, orally active small molecule neuroimmunophilin ligands promote neuronal recovery of degenerated neurones and define a novel class of therapeutic agents for the treatment of neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease.

• Alzheimer’s disease
• FKBP
• immunophilins
• neurodegenerative disorders
• neuroimmunophilins
• neuroregeneration
• neurotrophic
• Parkinson’s disease