A number of disease states of the eye manifest from malfunctioning enzymes or proteins involved in the visual cycle. Visual cycle modulation (VCM) has emerged as a promising therapeutic strategy for retinal diseases. Unfortunately, current VCM drug candidates have been found to be minimally effective due to their sub-optimal efficacy, short elimination half-life and tendency to produce visual side effects. The visual cycle is a metabolic pathway that generates, 11-cis-retinaldehyde (RAL) for rod and cone opsins, allowing the formation of visual pigments.In Stargardt’s disease, due to mutation in the ATP-binding cassette transporter 4 (ABCA4) results in the accumulation of all-trans retinal (atRAL) in the photoreceptor. The consequence of atRAL accumulation is the formation of the lipofuscin molecule A2E. A2E is a biomarker for the progression of a number of disease states of the eye including age-related macular degeneration. This provided a rational basis for developing specific inhibitors of visual cycle proteins. The amine derivative of retinal, retinylamine, inhibitor of retinoid isomerase, RPE65; membrane-bound enzyme catalyzes the conversion of all-trans-retinyl palmitate ester to 11-cis-retinol; was used as a basis for the development of emixustat, which is structurally similar non- retinoid. Emixustat inhibits substrate binding to the RPE65 active site . Retinol binding protein 4 (RBP4) is present in blood serum which is synthesized by liver acts as a transporter of retinol (Vitamin A) from liver to the eye. So, the other way is to slow down the transportation of Vitamin A into the eye which results in slowing visual cycle.

Visual cycle modulator (VCM) replacing vitamin A

Fluorescence binding assay on <i>gem-</i>difluoro-Emixustat

Fluorescence binding assay on gem-difluoro-Emixustat

Vivek Saraswat

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