A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration

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The retinoid visual cycle is an ocular retinoid metabolism specifically dedicated to support vertebrate vision. The visual cycle serves not only to generate light-sensitive visual chromophore 11-cis-retinal, but also to clear toxic byproducts of normal visual cycle (i.e. all-trans-retinal and its condensation products) from the retina, ensuring both the visual function and the retinal health. Unfortunately, various conditions including genetic predisposition, environment and aging may attribute to a functional decline of the all-trans-retinal clearance. To combat all-trans-retinal mediated retinal degeneration, we sought to slow down the retinoid influx from the RPE by inhibiting the visual cycle with a small molecule. The present study describes identification of CU239, a novel non-retinoid inhibitor of RPE65, a key enzyme in the visual cycle. Our data demonstrated that CU239 selectively inhibited isomerase activity of RPE65, with IC50 of 6 μM. Further, our results indicated that CU239 inhibited RPE65 via competition with its substrate all-trans-retinyl ester. Mice with systemic injection of CU239 exhibited delayed chromophore regeneration after light bleach, and conferred a partial protection of the retina against injury from high intensity light. Taken together, CU239 is a potent visual cycle modulator and may have a therapeutic potential for retinal degeneration.




Shin, Y., Moiseyev, G., Petrukhin, K., Cioffi, C. L., Muthuraman, P., Takahashi, Y., & Ma, J. xing. (2018). A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864(7), 2420–2429. https://doi.org/10.1016/j.bbadis.2018.04.014

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