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

Yuanyuan Chen (), Yu Chen, Beata Jastrzebska, Marcin Golczak, Sahil Gulati, Hong Tang, William Seibel, Xiaoyu Li, Hui Jin, Yong Han, Songqi Gao, Jianye Zhang, Xujie Liu, Hossein Heidari-Torkabadi, Phoebe L. Stewart, William E. Harte, Gregory P. Tochtrop and Krzysztof Palczewski ()
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Yuanyuan Chen: Case Western Reserve University
Yu Chen: Case Western Reserve University
Beata Jastrzebska: Case Western Reserve University
Marcin Golczak: Case Western Reserve University
Sahil Gulati: Case Western Reserve University
Hong Tang: University of Cincinnati
William Seibel: University of Cincinnati
Xiaoyu Li: Case Western Reserve University
Hui Jin: Case Western Reserve University
Yong Han: Case Western Reserve University
Songqi Gao: Case Western Reserve University
Jianye Zhang: Case Western Reserve University
Xujie Liu: University of Pittsburgh
Hossein Heidari-Torkabadi: Case Western Reserve University
Phoebe L. Stewart: Case Western Reserve University
William E. Harte: Case Western Reserve University
Gregory P. Tochtrop: Case Western Reserve University
Krzysztof Palczewski: Case Western Reserve University

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04261-1

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