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PDBsum entry 5a0e
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References listed in PDB file
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Key reference
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Title
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Selective inhibition of the mitochondrial permeability transition pore protects against neurodegeneration in experimental multiple sclerosis.
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Authors
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J.Warne,
G.Pryce,
J.M.Hill,
X.Shi,
F.Lennerås,
F.Puentes,
M.Kip,
L.Hilditch,
P.Walker,
M.I.Simone,
A.W.Chan,
G.J.Towers,
A.R.Coker,
M.R.Duchen,
G.Szabadkai,
D.Baker,
D.L.Selwood.
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Ref.
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J Biol Chem, 2016,
291,
4356-4373.
[DOI no: ]
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PubMed id
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Abstract
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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.
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