The standard-of-care therapeutics for the treatment of ocular neovascular diseases like wet age-related macular degeneration (AMD) are biologics targeting vascular endothelial growth factor signaling. There are currently no FDA approved small molecules for treating these blinding eye diseases. Therefore, therapeutic agents with novel mechanisms are critical to complement or combine with existing approaches. Here, we identified soluble epoxide hydrolase (sEH), a key enzyme for epoxy fatty acid metabolism, as a target of an antiangiogenic homoisoflavonoid, SH-11037. SH-11037 inhibits sEH in vitro and in vivo and docks to the substrate binding cleft in the sEH hydrolase domain. sEH levels and activity are up-regulated in the eyes of a choroidal neovascularization (CNV) mouse model. sEH is overexpressed in human wet AMD eyes, suggesting that sEH is relevant to neovascularization. Known sEH inhibitors delivered intraocularly suppressed CNV. Thus, by dissecting a bioactive compound’s mechanism, we identified a new chemotype for sEH inhibition and characterized sEH as a target for blocking the CNV that underlies wet AMD.

中文翻译：

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化学蛋白质组学揭示了可溶性环氧水解酶作为眼新血管形成的治疗靶标

用于治疗诸如湿性年龄相关性黄斑变性（AMD）等眼部新血管疾病的护理标准疗法是靶向血管内皮生长因子信号转导的生物制剂。目前尚无FDA批准的用于治疗这些致盲眼病的小分子。因此，具有新颖机制的治疗剂对于补充或与现有方法结合至关重要。在这里，我们确定了可溶性环氧化物水解酶（sEH），它是环氧脂肪酸代谢的关键酶，是抗血管生成同型异黄酮类化合物SH-11037的靶标。SH-11037抑制了sEH体外和体内并停靠在sEH水解酶结构域中的底物结合裂缝上。在脉络膜新血管形成（CNV）小鼠模型的眼睛中，sEH水平和活性上调。sEH在人类湿性AMD眼中过表达，表明sEH与新血管形成有关。已知的sEH抑制剂递送眼内抑制的CNV。因此，通过解剖生物活性化合物的机制，我们确定了sEH抑制的新化学型，并将sEH表征为阻断湿AMD基础CNV的靶标。