A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration

• Published in: Nature communications Vol. 9; no. 1; pp. 1976 - 18
• Main Authors: Chen, Yuanyuan, Chen, Yu, Jastrzebska, Beata, Golczak, Marcin, Gulati, Sahil, Tang, Hong, Seibel, William, Li, Xiaoyu, Jin, Hui, Han, Yong, Gao, Songqi, Zhang, Jianye, Liu, Xujie, Heidari-Torkabadi, Hossein, Stewart, Phoebe L, Harte, William E, Tochtrop, Gregory P, Palczewski, Krzysztof
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 17.05.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alcohol Oxidoreductases - genetics; Animals; ATP-Binding Cassette Transporters - genetics; Cell Line, Tumor; Cell survival; Cytotoxicity; Degeneration; Disease Models, Animal; Diterpenes; Female; HEK293 Cells; High-Throughput Screening Assays; Homeostasis; Humans; Light - adverse effects; Light effects; Male; Mammalian cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular chains; Mutants; Mutation; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; NIH 3T3 Cells; Pharmacology; Photoreceptors; Protein Folding - drug effects; Protein Transport - drug effects; Protein Transport - genetics; Retina; Retinal degeneration; Retinal Degeneration - drug therapy; Retinal Degeneration - etiology; Retinal Degeneration - pathology; Retinal Rod Photoreceptor Cells - drug effects; Retinal Rod Photoreceptor Cells - metabolism; Retinal Rod Photoreceptor Cells - pathology; Retinal Rod Photoreceptor Cells - radiation effects; Retinaldehyde - pharmacology; Retinaldehyde - therapeutic use; Retinitis; Retinitis pigmentosa; Rhodopsin; Rhodopsin - agonists; Rhodopsin - antagonists & inhibitors; Rhodopsin - genetics; Rhodopsin - metabolism; Thiophenes - pharmacology; Thiophenes - therapeutic use; Toxicity; Treatment Outcome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04261-1

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 EC 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.