Warne 2015 J Biol Chem
|Warne J, Pryce G, Hill JM, Shi X, Lennerås F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI, Chan AWE, Towers GJ, Coker AR, Duchen MR, Szabadkai G, Baker D, Selwood DL (2015) Selective inhibition of the mitochondrial permeability transition pore protects against neuro-degeneration in experimental multiple sclerosis. J Biol Chem 291:4356-73.|
Warne Justin, Pryce Gareth, Hill Julia M, Shi Xiao, Lenneraas Felicia, Puentes Fabiola, Kip Maarten, Hilditch Laura, Walker Paul, Simone Michela I, Chan AW Edith, Towers Greg J, Coker Alun R, Duchen Michael R, Szabadkai Gyorgy, Baker David, Selwood David L (2015) J Biol Chem
Abstract: The mitochondrial permeability transition pore (PT pore) is a recognised drug target for neurodegenerative conditions such as multiple sclerosis (MS) and for ischaemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, ppif) is a positive regulator of the pore and genetic downregulation or knockout improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off target effects, immune-suppression and toxicity. We therefore designed and synthesised a new mitochondrially-targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine (CsA). X-ray analysis was used to validate the design concept and biological evaluation revealed selective cellular inhibition of CypD and the PT pore with reduced cellular toxicity compared to CsA. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis (MS), JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.
• Keywords: EAE, X-ray crystallography, Cyclophilin D, Cyclosporin, Mitochondrial permeability transition (MPT), Mitochondrial targeting, Multiple sclerosis, Neurodegeneration, Neurodegenerative disease, Calcium retention capacity
• O2k-Network Lab: UK London Duchen MR
Labels: MiParea: Respiration, mt-Membrane Pathology: Neurodegenerative Stress:Permeability transition Organism: Mouse Tissue;cell: Liver Preparation: Isolated mitochondria
Regulation: Inhibitor Coupling state: LEAK, OXPHOS, ET Pathway: N, ROX HRR: Oxygraph-2k