- 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;
- Harte, William;
- Tochtrop, Gregory;
- Palczewski, Krzysztof
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.