| First Author | Chen Y | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 1976 |
| PubMed ID | 29773803 | Mgi Jnum | J:262864 |
| Mgi Id | MGI:6161147 | Doi | 10.1038/s41467-018-04261-1 |
| Citation | Chen Y, et al. (2018) A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration. Nat Commun 9(1):1976 |
| abstractText | 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. |
