Retinoids and Retinal Diseases

Abstract

Recent progress in molecular understanding of the retinoid cycle in mammalian retina stems from painstaking biochemical reconstitution studies supported by natural or engineered animal models with known genetic lesions and studies of humans with specific genetic blinding diseases. Structural and membrane biology have been used to detect critical retinal enzymes and proteins and their substrates and ligands, placing them in a cellular context. These studies have been supplemented by analytical chemistry methods that have identified small molecules by their spectral characteristics, often in conjunction with the evaluation of models of animal retinal disease. It is from this background that rational therapeutic interventions to correct genetic defects or environmental insults are identified. Thus, most presently accepted modulators of the retinoid cycle already have demonstrated promising results in animal models of retinal degeneration. These encouraging signs indicate that some human blinding diseases can be alleviated by pharmacological interventions.

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

“…This compound could be given at doses that protect mice against retinal phototoxicity with much fewer potent effects on visual cycle function as compared with emixustat. The origin of the residual effects on in vivo visual cycle function remains to be elucidated but these could arise from inhibition of visual cycle enzymes other than RPE65, including retinol dehydrogenases and lecithin:retinol acyltransferase (Kiser et al, 2014;Kiser and Palczewski, 2016). This work highlights the importance of thorough counter-screening of lead candidates at different levels, including in vivo assays to ensure productive drug development.…”

Hydrogen/Deuterium Exchange Mass Spectrometry of Human Green Opsin Reveals a Conserved Pro-Pro Motif in Extracellular Loop 2 of Monostable Visual G Protein-Coupled Receptors

“…3,4 All four pigments are activated by the isomerization of the chromophore 11- cis -retinal to all- trans -retinal, which is then released and regenerated back to 11- cis -retinal through the retinoid cycle. 5 Chromophore photoisomerization induces conformational changes in these light sensitive GPCRs and initiates the binding of the G proteins, transducins. 6–8 The two different conformational states, active and inactive, are known to be very stable and discrete in rhodopsin.…”

Visual cycle proteins: Structure, function, and roles in human retinal disease

“…Isomerization of 11-cis-retinal into all-transretinal by light sets off a cascade of opsin conformational changes that leads to the formation of metarhodopsin II (Meta II), and activates the associated G proteins. This signal is transduced to a cyclic guanosine monophosphate (cGMP) second messenger resulting in a change in the level of 5'GMP and the closure of cation channels (9,10 (11). IRBP is composed of multiple modules (4 in tetrapods and human, and 2 to 3 modules in teleosts) with each harboring ~300 amino acid residues (11).…”

“…Pharmacological Approach: Some have recommended the use of vitamin A and fish oils to help reduce progression of RP in adults, but this remains controversial as to its effectiveness (30,49,50). Although the use of retinoid isomers and visual cycle inhibitors have shown to be effective in research studies (9), no pharmaceutical treatments are available currently approved for retinal diseases such as LCA or STGD. Targets for pharmaceuticals such as -cyclodextrins are being investigated in an effort to enhance photoreceptor survival in individuals suffering from these maladies (43).…”