Pharmacochaperones as a novel approach to rescue misfolding rod opsin mutants associated with retinitis pigmentosa.

Abstract

The correct trafficking of folded, functional rhodopsin (Rho) is critical to sustaining vision. Inherited destabilizing mutations in the rhodopsin (RHO) gene lead to a spectrum of blinding diseases called retinitis pigmentosa (RP) with currently no cure available. Therapeutic approaches to correct these impartments focus on the development of pharmacological chaperones that stabilize rod opsin. The native ligand, 11-cis-retinal, improves protein stability, folding, and trafficking of some mutated Rho variants. However, its chemical instability, toxicity, and poor pharmacokinetics limit its use as a therapeutic. In our laboratory, we focus our attention on finding chaperones with natural-like product scaffolds due to their broad chemical diversity. Furthermore, ∼50% of marketed small molecule drugs are derived from natural products scaffold, and some of them target GPCRs. Thus, we integrated computational, biochemical, biophysical, and in vivo analysis to evaluate non-retinoid ligands with diverse chemical scaffolds as potential chaperones of misfolding Rho variants. Our study led to the discovery of a novel chromenone-containing small molecule with favorable pharmacological properties that through direct binding to the orthosteric pocket enhanced rod opsin stability. This compound improved the membrane trafficking of multiple rod opsin mutants in vitro. Importantly, our studies unraveled the pharmacological potential of this new chromenone rod opsin ligand to slow down the progression of photoreceptor degeneration in the P23H Rho knock-in mice, a model of RP. Together, our studies encourage further search and evaluation of novel non-retinoid compounds that could mitigate the misfolding and mistrafficking of the Rho mutants to prolong the survival of photoreceptors in the retina, and thus delaying vision loss in RP.