Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea.
School of Medicine, Yanbian University, College of Pharmacy, Yanbian University, Park Road, 977, Yanji 133002, Jilin Province, People's Republic of China.
Biochem Pharmacol. 2023 May;211:115534. doi: 10.1016/j.bcp.2023.115534. Epub 2023 Apr 4.
Dry age-related macular degeneration (AMD) is a type of disease that causes visual impairment due to changes in the macula located in the center of the retina. The accumulation of drusen under the retina is also a characteristic of dry AMD. In this study, we identified a compound (JS-017) that can potentially degrade N-retinylidene-N-retinylethanolamine (A2E), one of the components of lipofuscin, using fluorescence-based screening, which measures A2E degradation in human retinal pigment epithelial cells. JS-017 effectively degraded A2E in ARPE-19 cells and consequently suppressed the activation of the NF-κB signaling pathway and expression of inflammatory and apoptosis genes induced by blue light (BL). Mechanistically, JS-017 induced LC3-II formation and improved autophagic flux in ARPE-19 cells. Additionally, the A2E degradation activity of JS-017 was found to be decreased in autophagy-related 5 protein-depleted ARPE-19 cells, suggesting that autophagy was required for A2E degradation mediated by JS-017. Finally, JS-017 exhibited an improvement in BL-induced retinal damage measured through fundus examination in an in vivo retinal degeneration mouse model. The thickness of the outer nuclear layer and inner/external segments, which was decreased upon exposure to BL irradiation, was also restored upon JS-017 treatment. Altogether, we demonstrated that JS-017 protected human retinal pigment epithelium (RPE) cells from A2E and BL-induced damage by degrading A2E via the activation of autophagy. The results suggest the feasibility of a novel A2E-degrading small molecule as a therapeutic agent for retinal degenerative diseases.
干性年龄相关性黄斑变性（AMD）是一种由于位于视网膜中心的黄斑发生变化而导致视力损害的疾病。视网膜下脂褐素的沉积物也是干性 AMD 的特征之一。在这项研究中，我们使用荧光筛选法鉴定出一种化合物（JS-017），它可以潜在地降解 N-视黄基-N-视黄基乙醇胺（A2E），这是脂褐素的一种成分。JS-017 可以有效地在 ARPE-19 细胞中降解 A2E，从而抑制由蓝光（BL）诱导的 NF-κB 信号通路的激活和炎症及凋亡基因的表达。在机制上，JS-017 诱导 ARPE-19 细胞中 LC3-II 的形成，并改善自噬流。此外，在自噬相关蛋白 5 耗尽的 ARPE-19 细胞中，JS-017 的 A2E 降解活性降低，表明自噬是 JS-017 介导的 A2E 降解所必需的。最后，JS-017 在体内视网膜变性小鼠模型中通过眼底检查显示出对 BL 诱导的视网膜损伤的改善。BL 照射后外核层和内/外节的厚度减少，经 JS-017 处理后也得到恢复。总之，我们证明了 JS-017 通过激活自噬来降解 A2E，从而保护人视网膜色素上皮（RPE）细胞免受 A2E 和 BL 诱导的损伤。结果表明，一种新型的 A2E 降解小分子作为治疗视网膜退行性疾病的药物具有可行性。
