RPE65-61 ((±)-RPE65-61) is a selective, non-retinoid and uncompetitive inhibitor of RPE65 (a key enzyme in the visual cycle), inhibits the retinol isomerase activity of RPE65 in vitro with IC50 of 80 nM.
(±)-RPE65-61 (375 nM) resulted in a significant decrease of 11-cis-retinol production in in vitro isomerase test using bovine RPE microsomes, did not suppress the production of retinyl ester implying that ecithin retinol acyltransferase (LRAT) was not inhibited.
(±)-RPE65-61 also showed no activity in the Retinol-Binding Protein 4 (RBP4) binding assays.
(±)-RPE65-61 (2 mg/kg, i.p.) delayed chromophore regeneration, reduced 11-cis-retinal and rhodopsin regeneration in the mouse eye in BALB/cJ mice, with higher levels of all-trans-retinyl ester, RPE65's substrate, indicating reduced RPE65 activity.
(±)-RPE65-61 (2 mg/kg, i.p.) prevented declines of retinal thickness induced by light damage, preserved photoreceptors in light-induced retinal damage (LIRD) model.
(±)-RPE65-61 down-regulated the cGAS-STING pathway, decreased the inflammatory factor, and attenuated retinal apoptosis caused by LIRD, which led to the preservation of the retinal function.