A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration PMID: 29773803

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2018 May 17;9(1):1976. doi: 10.1038/s41467-018-04261-1.

Yuanyuan Chen ¹ ² ³ , Yu Chen ⁴ ⁵ , Beata Jastrzebska ⁴ ⁶ , Marcin Golczak ⁴ ⁶ , Sahil Gulati ⁴ ⁶ , Hong Tang ⁷ , William Seibel ⁷ , Xiaoyu Li ⁴ , Hui Jin ⁴ , Yong Han ⁸ , Songqi Gao ⁴ , Jianye Zhang ⁴ , Xujie Liu ⁹ , Hossein Heidari-Torkabadi ⁴ , Phoebe L Stewart ⁴ ⁶ , William E Harte ¹⁰ , Gregory P Tochtrop ⁸ , Krzysztof Palczewski ¹¹ ¹²

Affiliations

1. Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. [email protected].
2. The McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive Suite 300, Pittsburgh, PA, 15219, USA. [email protected].
3. Department of Ophthalmology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA. [email protected].
4. Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
5. Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 200437, Shanghai, China.
6. Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, 1819 E. 101st Street, Cleveland, OH, 44106, USA.
7. Drug Discovery Center, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, OH, 45237, USA.
8. Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
9. Department of Ophthalmology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA.
10. Office of Translation and Innovation, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
11. Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. [email protected].
12. Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, 1819 E. 101st Street, Cleveland, OH, 44106, USA. [email protected].

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.