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

Biochim Biophys Acta Mol Basis Dis. 2018 Jul;1864(7):2420-2429. doi: 10.1016/j.bbadis.2018.04.014. Epub 2018 Apr 21.


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.

Keywords: Age-related macular degeneration; Enzyme inhibitor; RPE65; Retinal degeneration; Stargardt's disease; Visual cycle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diterpenes
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Retinal Degeneration* / drug therapy
  • Retinal Degeneration* / enzymology
  • Retinal Degeneration* / genetics
  • Retinal Degeneration* / pathology
  • Retinyl Esters
  • Vision, Ocular* / drug effects
  • Vision, Ocular* / genetics
  • Vitamin A / analogs & derivatives
  • Vitamin A / metabolism
  • cis-trans-Isomerases* / antagonists & inhibitors
  • cis-trans-Isomerases* / genetics
  • cis-trans-Isomerases* / metabolism


  • Diterpenes
  • Enzyme Inhibitors
  • Retinyl Esters
  • Vitamin A
  • retinol acetate
  • retinoid isomerohydrolase
  • cis-trans-Isomerases