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Biological Chemistry

Accutane Aids Design of Drugs for Macular Degeneration

July 19, 2004 | A version of this story appeared in Volume 82, Issue 29

Accutane (13-cis-retinoic acid) is used to treat severe, scarring acne, but it can also cause vision problems. New work shows that this unfortunate side effect is caused by 13-cis-retinoic acid inhibiting the vision cycle protein RPE65.

The identification of Accutane's precise molecular target in the eye will facilitate the design of drugs that partially inhibit the vision cycle, according to professor of biological chemistry and molecular pharmacology Robert R. Rando of Harvard Medical School. Such drugs might make much-needed treatments for certain forms of macular and retinal degenerative diseases, he adds.

Although 13-cis-retinoic acid had previously been shown to inhibit the vision cycle, its primary protein target has remained elusive. Now, Rando and postdoc Deviprasad R. Gollapalli have used a quantitative fluorescence binding assay to demonstrate that 13-cis-retinoic acid's vision target is RPE65 [Proc. Natl. Acad. Sci. USA,101, 10030 (2004)].

RPE65 plays a crucial rate-limiting role in the vision cycle. The protein chaperones a highly hydrophobic cycle intermediate (all-trans-retinyl esters) to the next enzyme in the cycle. Accutane binds RPE65 with nanomolar affinity and competes with all-trans-retinyl esters binding to the protein, Rando and Gollapalli find. This competition inhibits processing of all-trans-retinyl esters into the rhodopsin chromophore that's required for vision. As a consequence, some patients taking Accutane find it difficult to see in low-light situations, a condition known as night blindness.

Rando hopes to use 13-cis-retinoic acid as a starting point to design molecules that partially inhibit the vision cycle. He notes that a number of macular and retinal degenerative diseases are caused by the formation of highly toxic by-products from chemically reactive vision cycle intermediates. For instance, highly reactive all-trans-retinal can combine with the common membrane lipid phosphatidyl ethanolamine to produce A2E, an accumulation of which is associated with Stargardt's disease, a hereditary kind of macular degeneration.

Partially inhibiting RPE65 and thus the vision cycle with a retinoic-acid-like molecule would reduce the accumulation of such toxic by-products, Rando suggests. Such molecules might be useful in treating these eye diseases. "It should be readily possible to design potent and specific antagonists of RPE65 that don't have the toxic side effects of retinoic acid," which include birth defects and even fetal death, he says. In addition, he suggests that screening 13-cis-retinoic acid analogs for variants that don't bind RPE65 could turn up an acne drug that doesn't cause vision problems.



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