Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis

J Biol Chem. 2016 Feb 26;291(9):4356-73. doi: 10.1074/jbc.M115.700385. Epub 2015 Dec 17.

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / immunology
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Cyclophilins / antagonists & inhibitors*
  • Cyclophilins / genetics
  • Cyclophilins / metabolism
  • Cyclosporins / adverse effects
  • Cyclosporins / chemical synthesis
  • Cyclosporins / pharmacology
  • Cyclosporins / therapeutic use
  • Hep G2 Cells
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors*
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • Multiple Sclerosis / prevention & control*
  • Mutation
  • Neurons / drug effects*
  • Neurons / immunology
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Peptides, Cyclic / adverse effects
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / pharmacology
  • Peptides, Cyclic / therapeutic use
  • Peptidyl-Prolyl Isomerase F
  • Quinolinium Compounds / adverse effects
  • Quinolinium Compounds / chemical synthesis
  • Quinolinium Compounds / pharmacology
  • Quinolinium Compounds / therapeutic use*
  • Random Allocation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / pathology

Substances

  • Peptidyl-Prolyl Isomerase F
  • Cyclosporins
  • JW47 compound
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Neuroprotective Agents
  • PPIF protein, mouse
  • Peptides, Cyclic
  • Quinolinium Compounds
  • Recombinant Proteins
  • Cyclophilins

Associated data

  • PDB/2Z6W
  • PDB/4IPZ
  • PDB/5A0E