A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Shin, Younghwa¹  Moiseyev, Gennadiy¹  Petrukhin, Konstantin³  Cioffi, Christopher L.^4,5  Muthuraman, Parthasarathy^4,5  Takahashi, Yusuke²  Ma, Jian-xing¹ 

[1] Univ Oklahoma, Hlth Sci Ctr, Dept Physiol, Oklahoma City, OK 73104 USA

[2] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK 73104 USA

[3] Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA

[4] Albany Coll Pharm & Hlth Sci, Dept Basic & Clin Sci, Albany, NY 12208 USA

[5] Albany Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Albany, NY 12208 USA

关键词: Age-related macular degeneration;    Enzyme inhibitor;    Retinal degeneration;    RPE65;    Stargardt's disease;    Visual cycle;   

DOI  :  10.1016/j.bbadis.2018.04.014

来源: Elsevier

【 摘 要 】

The retinoid visual cycle is an ocular retinoid metabolism specifically dedicated to support vertebrate vision. The visual cycle serves not only to generate light-sensitive visual chromophore 11-cis-retinal, but also to clear toxic byproducts of normal visual cycle (Le. all-trans-retinal and its condensation products) from the retina, ensuring both the visual function and the retinal health. Unfortunately, various conditions including genetic predisposition, environment and aging may attribute to a functional decline of the all-trans-retinal clearance. To combat all-trans-retinal mediated retinal degeneration, we sought to slow down the retinoid influx from the RPE by inhibiting the visual cycle with a small molecule. The present study describes identification of CU239, a novel non-retinoid inhibitor of RPE65, a key enzyme in the visual cycle. Our data demonstrated that CU239 selectively inhibited isomerase activity of RPE65, with IC50 of 6 mu M. Further, our results indicated that CU239 inhibited RPE65 via competition with its substrate all-trans-retinyl ester. Mice with systemic injection of CU239 exhibited delayed chromophore regeneration after light bleach, and conferred a partial protection of the retina against injury from high intensity light. Taken together, CU239 is a potent visual cycle modulator and may have a therapeutic potential for retinal degeneration.

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