Selective inhibition of the mitochondrial permeability transition pore protects against neuro-degeneration in experimental multiple sclerosis

DOI: 10.1074/jbc.M115.700385
PMID: 26679998

Authors: Justin Warne (University College London) , Gareth Pryce (University of London) , Julia Hill (University College London) , Xiao Shi (University College London) , Felicia Lennerås (University of London) , Fabiola Puentes (University of London) , Maarten Kip (University College London) , Laura Hilditch (University College London) , Paul Walker (Cyprotex Ltd) , Michela I. Simone (University of Newcastle) , A. W. Edith Chan (University College London) , Greg J. Towers (University College London) , Alun Coker (University College London) , Michael R. Duchen (University College London) , Gyorgy Szabadkai (University College London) , David Baker (University of London) , David L. Selwood (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 291

State: Published (Approved)
Published: December 2015
Diamond Proposal Number(s): 8922

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.

Journal Keywords: cyclophilin D; mitochondrial permeability transition (MPT); multiple sclerosis; neurodegeneration; neurodegenerative disease; X-ray crystallography; EAE; cyclosporin; mitochondrial targeting

Diamond Keywords: Multiple Sclerosis

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 04/01/2016 10:09

Documents:
PIIS0021925820435847.pdf

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Neurology Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)