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bioRxiv · 10.1101/2022.04.05.487228

Chromenone derivatives as novel pharmacological chaperones for retinitis pigmentosa-linked rod opsin mutants

Ortega, J. T.·McKee, A. G.·Roushar, F. J.·Penn, W. D.·Schlebach, J. P.·Jastrzebska, B.
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Abstract

The correct expression of folded, functional rhodopsin (Rho) is critical for visual perception. However, this seven-transmembrane helical G protein-coupled receptor (GPCR) is prone to mutations with pathological consequences of retinal degeneration in retinitis pigmentosa (RP) due to Rho misfolding. Pharmacological chaperones that stabilize the inherited Rho variants by assisting their folding and membrane targeting could slow the progression of RP. In this study, we employed virtual screening of synthetic compounds with natural product scaffold in conjunction with in vitro and in vivo evaluations to discover a novel chromenone-containing small molecule with favorable pharmacological properties that stabilizes rod opsin. This compound reversibly binds to unliganded bovine rod opsin with an EC50 value comparable to the 9-cis-retinal chromophore analog and partially rescued membrane trafficking of multiple RP-related rod opsin variants in vitro. Importantly, this novel ligand of rod opsin was effective in vivo in murine models, protecting photoreceptors from deterioration caused either by bright light or genetic insult. Together, our current study suggests potential broad therapeutic implications of the new chromenone-containing non-retinoid small molecule against retinal diseases associated with photoreceptor degeneration.

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Ortega, J. T., McKee, A. G., Roushar, F. J., Penn, W. D., Schlebach, J. P., Jastrzebska, B.. 2022-04-08. Chromenone derivatives as novel pharmacological chaperones for retinitis pigmentosa-linked rod opsin mutants. https://doi.org/10.1101/2022.04.05.487228

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