9DQA

Crystal structure of bovine RPE65 in complex with EYE-002

This is a non-PDB format compatible entry.

Summary for 9DQA

• Entry DOI: 10.2210/pdb9dqa/pdb
• Descriptor: Retinoid isomerohydrolase, FE (II) ION, PALMITIC ACID, ... (5 entities in total)
• Functional Keywords: 7-bladed beta propeller, monotopic membrane protein, non-heme iron enzyme, retinoid isomerase, inhibitor, complex, hydrolase, isomerase, isomerase-inhibitor complex, isomerase/inhibitor
• Biological source: Bos taurus (domestic cattle)
• Total number of polymer chains: 2
• Total formula weight: 123235.62

Authors

Kiser, P.D.,Bassetto, M. (deposition date: 2024-09-23, release date: 2025-09-03, Last modification date: 2025-09-10)

Primary citation

Bassetto, M.,Hu, Y.,Li, B.,Chen, X.,Saraswat, V.,Damacio, F.,Smidak, R.,Palczewski, K.,Tochtrop, G.P.,Kiser, P.D.
Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies.
J.Med.Chem., 68:17638-17652, 2025

PubMed Abstract: The visual cycle is a metabolic pathway essential for visual function. The bisretinoid byproducts of this pathway can induce retinal toxicity, as occurs in Stargardt disease type 1 (STGD1). Emixustat, which inhibits bisretinoid production, is a visual cycle modulator (VCM) that targets RPE65. However, it causes visual impairment due to its unfavorable duration of action. Here, we report ester-containing analogs of emixustat that are susceptible to hydrolytic clearance and function as short-acting VCMs. We show that the esterase-mediated metabolism of these compounds can be tuned while maintaining high-affinity RPE65 targeting. Compounds (EYE-002) and (EYE-003) containing diethyl acetate and valproate esters, respectively, allowed faster recovery of visual cycle function compared to emixustat. These molecules protected against retinal degeneration in mouse models of photic retinopathy and STGD1. These data demonstrate that shorter attenuation of the visual cycle can therapeutically intervene in retinal diseases with fewer visual side effects compared to emixustat.

PubMed: 40764714
DOI: 10.1021/acs.jmedchem.5c01353

Experimental method

X-RAY DIFFRACTION (2.1 Å)