title: Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.
abstract: The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out 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, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, 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.
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Justin
authors.initials: J
authors.lastname: Warne
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom, the Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Pryce
authors.affiliation: the Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Hill
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Xiao
authors.initials: X
authors.lastname: Shi
authors.affiliation: the Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom.
authors.forename: Felicia
authors.initials: F
authors.lastname: Lennerås
authors.affiliation: the Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Puentes
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Maarten
authors.initials: M
authors.lastname: Kip
authors.affiliation: the Medical Research Council Centre for Medical Molecular Biology, Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Hilditch
authors.affiliation: Cyprotex Discovery Ltd., 100 Barbirolli Square, Manchester M2 3AB, United Kingdom, and.
authors.forename: Paul
authors.initials: P
authors.lastname: Walker
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Michela I
authors.initials: MI
authors.lastname: Simone
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: A W Edith
authors.initials: AW
authors.lastname: Chan
authors.affiliation: the Medical Research Council Centre for Medical Molecular Biology, Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Alun R
authors.initials: AR
authors.lastname: Coker
authors.affiliation: the Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: the Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom, the Department of Biomedical Sciences, University of Padua, Padua 35122, Italy.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Szabadkai
authors.affiliation: the Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom, david.baker@qmul.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom, d.selwood@ucl.ac.uk.
authors.forename: David L
authors.identifier: http://orcid.org/0000-0002-6817-5064
authors.initials: DL
authors.lastname: Selwood
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003524:Cyclosporins / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009154:Mutation; D009474:Neurons / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011806:Quinolinium Compounds / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D003524:Cyclosporins; C000609419:JW47 compound; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; C000631446:PPIF protein, mouse; D010456:Peptides, Cyclic; D011806:Quinolinium Compounds; D011994:Recombinant Proteins; D021983:Cyclophilins
keywords: EAE; X-ray crystallography; cyclophilin D; cyclosporin; mitochondrial permeability transition (MPT); mitochondrial targeting; multiple sclerosis; neurodegeneration; neurodegenerative disease