Abstract
Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001. As a non-retinoid molecule, YC-001 demonstrates micromolar potency and efficacy greater than 9-cis-retinal with lower cytotoxicity. YC-001 binds to bovine rod opsin with an EC50 similar to 9-cis-retinal. The chaperone activity of YC-001 is evidenced by its ability to rescue the transport of multiple rod opsin mutants in mammalian cells. YC-001 is also an inverse agonist that non-competitively antagonizes rod opsin signaling. Significantly, a single dose of YC-001 protects Abca4 -/- Rdh8 -/- mice from bright light-induced retinal degeneration, suggesting its broad therapeutic potential.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / genetics
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Alcohol Oxidoreductases / genetics
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Animals
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Cell Line, Tumor
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Disease Models, Animal
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Diterpenes
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Female
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HEK293 Cells
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High-Throughput Screening Assays
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Humans
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Light / adverse effects
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation
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NIH 3T3 Cells
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Protein Folding / drug effects*
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Protein Transport / drug effects
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Protein Transport / genetics
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Retinal Degeneration / drug therapy*
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Retinal Degeneration / etiology
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Retinal Degeneration / pathology
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Retinal Rod Photoreceptor Cells / drug effects*
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Retinal Rod Photoreceptor Cells / metabolism
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Retinal Rod Photoreceptor Cells / pathology
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Retinal Rod Photoreceptor Cells / radiation effects
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Retinaldehyde / pharmacology
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Retinaldehyde / therapeutic use
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Rhodopsin / agonists
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Rhodopsin / antagonists & inhibitors
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Rhodopsin / genetics
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Rhodopsin / metabolism*
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Thiophenes / pharmacology*
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Thiophenes / therapeutic use
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Treatment Outcome
Substances
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ATP-Binding Cassette Transporters
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Abca4 protein, mouse
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Diterpenes
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Neuroprotective Agents
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Thiophenes
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9-cis-retinal
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Rhodopsin
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Alcohol Oxidoreductases
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Rdh8 protein, mouse
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Retinaldehyde