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Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	Selective inhibition of the mitochondrial permeability transition pore protects against neuro-degeneration in experimental multiple sclerosis Justin Warne , Gareth Pryce , Julia Hill , Xiao Shi , Felicia Lennerås , Fabiola Puentes , Maarten Kip , Laura Hilditch , Paul Walker , Michela I. Simone , A. W. Edith Chan , Greg J. Towers , Alun Coker , Michael R. Duchen , Gyorgy Szabadkai , David Baker , David L. Selwood Journal Of Biological Chemistry 291 DOI: 10.1074/jbc.M115.700385 PMID: 26679998 Diamond Proposal Number(s): [8922] Open Access Show Abstract ▼ 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.	Dec 2015

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I04-Macromolecular Crystallography

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