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

作者：Shin Younghwa; Moiseyev Gennadiy^*; Petrukhin Konstantin; Cioffi Christopher L; Muthuraman Parthasarathy; Takahashi Yusuke; Ma Jian xing

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2018, 1864(7): 2420-2429.

DOI：10.1016/j.bbadis.2018.04.014

• Age-related macular degeneration
• Enzyme inhibitor
• Retinal degeneration
• RPE65
• Stargardt's disease
• Visual cycle

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 (Le. 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 mu M. 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.

• 出版日期2018-7