Retinitis Pigmentosa (RP) and Leber’s Congenital Amaurosis (LCA) are two of the most severe blinding diseases. Both of them can be caused by aggregation of the protein opsin, which transmits the visual signal in the retina. A cure for these conditions is not available. Opsin aggregation is caused by mutations in its gene or to the absence of 11-cis-retinal, the endogenous ligand that binds the protein and stabilises its structure. Our approach is to consider pathologic opsin aggregation as a protein conformational disease, and design new small-molecule chemical chaperones which help opsin stability and prevent the protein-protein interactions leading to aggregation. Using molecular modelling, different novel compounds with high predicted affinity for opsin have been identified. These compounds were synthesised and preliminary evaluated in a competitive binding assay using wild-type opsin and 9-cis-retinal. Several small-molecules were found to stabilise the protein and/or increase its affinity for the natural substrate, providing hits for structural optimisation. These results led to the selection of structural analogues of the initial hits to identify more potent stabilisers for opsin: the design, synthesis and evaluation for efficacy and safety in cellular assays of these new compounds will be discussed.

Development of novel treatments against inherited blinding diseases Retinitis pigmentosa and Leber’s congenital amaurosis

2019 Spring National Meeting

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