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Philip Kiser, Jianye Zhang, Mohsen Badiee, Gregory Tochtrop, Krzysztof Palczewski; Rational tuning of visual cycle modulator pharmacodynamics. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2970.
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© ARVO (1962-2015); The Authors (2016-present)
Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase RPE65 based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Recently, it was discovered that these agents reversibly form retinal-Schiff base adducts through their primary amine moieties, which also contributes to their retinal protective activity. Inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration whereas effective retinal sequestration can require high doses of drug with potential off-target effects. Here, we employed a structure-based approach to design retinal-sequestering visual cycle modulators with varying degrees of direct retinoid isomerase inhibitory activity.
RPE65-emixustat/MB-001 crystal structures were used to design primary amine compounds with varying degrees of complementarity to the RPE65 active site. These compounds were synthesized and tested for visual cycle inhibitory activity. In vivo formation of retinal Schiff-base adducts was studied using mass spectrometry. Efficacy in protecting the retina from light damage in Abca4-/-/Rdh8-/- mice was evaluated by OCT. Binding of compounds to the RPE65 active site cavity was studied by x-ray crystallography.
Appropriate substitutions to the emixustat core structure resulted in a series of compounds effectively lacking in vitro retinoid isomerase inhibitory activity, whereas substitutions of the cyclohexyl tail potentiated RPE65 inhibition. Crystal structures of the latter group of compounds in complex with RPE65 confirmed the mechanism of enhanced inhibition. The non-inhibitory derivative series produced discernible visual cycle suppression in vivo, albeit much less potently than emixustat. These agents maintained the capability to distribute into the retina and form Schiff base adducts. Most of the compounds conferred protection against retinal phototoxicity, suggesting that both direct RPE65 inhibition and retinal sequestration are both of therapeutic relevance.
These data support the idea that visual cycle suppression is not essential for the retinal protective effects of primary amine retinoid-mimetic compounds, a finding that has important implications for the use of visual cycle modulators in the treatment of retinal diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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