User:Ivan E. Wang/Sandbox Reserved 895
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= Introduction to the RPE65 = | = Introduction to the RPE65 = | ||
<StructureSection load='4rsc' size='500' side='right' caption='Figure 1: Emixustat and palmitate bound in the active site of RPE65' scene=''> | <StructureSection load='4rsc' size='500' side='right' caption='Figure 1: Emixustat and palmitate bound in the active site of RPE65' scene=''> | ||
| - | Retinal pigment epithelium 65 (RPE65) also known as retinoid isomerohydrolase is a 65 kDa enzyme located within the human retinal pigment epithelium cells. | + | |
| + | 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. | ||
</StructureSection> | </StructureSection> | ||
= Structure and Activity = | = Structure and Activity = | ||
| - | == Structural Analysis of RPE65 == | + | == Classification and Structural Analysis of RPE65 == |
| - | ( | + | |
| + | Classification nomenclature for RPE65 is as follow according to <insert classification type> | ||
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| + | 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. | ||
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== Enzymatic Activity of RPE65 == | == Enzymatic Activity of RPE65 == | ||
(PLACEHOLDER) | (PLACEHOLDER) | ||
| - | [[Image: | + | [[Image:Visual_Cycle_RPE.jpg|thumb|right|512 px|alt=Figure 2: Human Visual Cycle| Figure 2: The canonical Visual Cycle in Humans <ref>DOI 10.1016/j.bbadis.2018.04.014</ref>]] |
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=== (''R'')-Emixustat (ACU-4429) === | === (''R'')-Emixustat (ACU-4429) === | ||
<StructureSection load='4ryy' size='340' side='right' caption='Figure 3:(R)-emixustat and palmitate bound in the active site of RPE65' scene=''> | <StructureSection load='4ryy' size='340' side='right' caption='Figure 3:(R)-emixustat and palmitate bound in the active site of RPE65' scene=''> | ||
| - | (''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 such as A2E. | + | (''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. |
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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. | 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. | ||
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| + | 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. | ||
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</StructureSection> | </StructureSection> | ||
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= Medical Relevance = | = Medical Relevance = | ||
| - | ( | + | == Dry (atrophic) age related macular degeneration == |
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| + | == Stargadt's Disease == | ||
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | ||
Current revision
Contents |
Introduction to the RPE65
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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)
Image:Visual Cycle RPE.jpg
Figure 2: The canonical Visual Cycle in Humans [1]
Protein-Ligand Interaction
Endogenous Ligand
(PLACEHOLDER)
Exogenous Ligand
(R)-Emixustat (ACU-4429)
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(S)-Emixustat
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R/S Enantiomers Differences
(PLACEHOLDER)
Disease Implications
(PLACEHOLDER)
Medical Relevance
Dry (atrophic) age related macular degeneration
Stargadt's Disease
This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
References
- ↑ Shin Y, Moiseyev G, Petrukhin K, Cioffi CL, Muthuraman P, Takahashi Y, Ma JX. 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. PMID:29684583 doi:http://dx.doi.org/10.1016/j.bbadis.2018.04.014
