Abstract
Retinitis pigmentosa (RP) is an inherited retinal dystrophy that courses with progressive degeneration of retinal tissue and loss of vision. Currently, RP is an unpreventable, incurable condition. We propose glycogen synthase kinase 3 (GSK-3) inhibitors as potential leads for retinal cell neuroprotection, since the retina is also a part of the central nervous system and GSK-3 inhibitors are potent neuroprotectant agents. Using a chemical genetic approach, diverse small molecules with different potency and binding mode to GSK-3 have been used to validate and confirm GSK-3 as a pharmacological target for RP. Moreover, this medicinal chemistry approach has provided new leads for the future disease-modifying treatment of RP.
Keywords:
GSK-3 inhibitors; glaucoma; retinal diseases; retinitis pigmentosa.
MeSH terms
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Animals
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Cell Death / drug effects
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Mice
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Mice, Inbred C57BL
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Molecular Structure
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Retinitis Pigmentosa / drug therapy*
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Retinitis Pigmentosa / enzymology
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Retinitis Pigmentosa / metabolism
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
Substances
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Neuroprotective Agents
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Protein Kinase Inhibitors
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Small Molecule Libraries
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Glycogen Synthase Kinase 3
Grants and funding
This work has been partially funded by the Spanish MINECO grants (SAF2012-37979-C03-01 to AM and SAF2013-41059-R to EJdlR).