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Introduction to the RPE65

spinqualitylabelsall models Figure 1: Emixustat and palmitate bound in the active site of RPE65 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Retinal pigment epithelium 65 (RPE65) also known as retinoid isomerohydrolase (IMH) is a 65 kDa enzyme located within the human retinal pigment epithelium (hRPE) cells. RPE65 is exclusively expressed within hRPE cells and is not expressed anywhere else within the body which makes RPE65 a useful drug target. RPE65 is responsible for the chemical conversion of all-trans-retinyl ester to 11-cis-retinol, the rate limiting step, in the canonical visual cycle.

Structure and Activity

Classification and Structural Analysis of RPE65

Classification nomenclature for RPE65 is as follow according to <insert classification type>

Retinal pigment epithelium 65 (RPE65) resembles a 7-bladed propeller with two deep binding pockets that contains a lipophilic binding pocket (which binds to endogenous palmitoyl acid) as well as an charged iron(II) atom stabilized by 4 histidine residues (His180, His241, His313 and His527) which binds to the carboxylic acid functional group of endogenous palmitoyl acid.

Enzymatic Activity of RPE65

(PLACEHOLDER)

Figure 2: Human Visual Cycle

Figure 2: The canonical Visual Cycle in Humans

Protein-Ligand Interaction

Endogenous Ligand

(PLACEHOLDER)

Exogenous Ligand

(R)-Emixustat (ACU-4429)

spinqualitylabelsall models Figure 3:(R)-emixustat and palmitate bound in the active site of RPE65 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D (R)-emixustat (ACU-4429) is an investigational small molecule inhibitor of RPE65 first invented by a British-American chemist, Ian L. Scott. Formulated as an hydrochloride salt, (R)-emixustat hydrochloride is taken by mouth and functions as a visual cycle modulator (VCM) to reduce toxic retinal byproducts in the canonical visual cycle such as A2E. In 2008, Acucela Inc. partnered with Otsuka Pharmaceutical Company for the continued development of (R)-emixustat as a potential inhibitor of RPE65. Currently (R)-emixustat is in Phase III clinical trials in the United States for the potential treatment of Stargard's disease, a juvenile form of atrophic (dry) age dependent macular degeneration (AMD). Additionally, (R)-emixustat is investigated as potential therapy for diabetic retinopathy and diabetic macular edema. Historically (R)-Emixustat was tested as a possible treatment for dry (atrophic) age-related macular degeneration in Phase IIb/III clinical trials but failed to show clinical outcomes due to significant pharmacokinetic and pharmacodynamic short falls.

(S)-Emixustat

spinqualitylabelsall models Figure 4:(S)-emixustat and palmitate bound in the active site of RPE65 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D (PLACEHOLDER)

R/S Enantiomers Differences

(PLACEHOLDER)

Disease Implications

(PLACEHOLDER)

Medical Relevance

Stargadt's Disease

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Ivan E. Wang