Chemical Proteomics Reveals Soluble Epoxide Hydrolase as a Therapeutic Target for Ocular Neovascularization.
Chemical Proteomics Reveals Soluble Epoxide Hydrolase as a Therapeutic Target for Ocular Neovascularization.
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化学蛋白质组学揭示可溶性环氧化物水解酶作为眼部新生血管的治疗靶点。
DOI：
10.1021/acschembio.7b00854
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发表时间：
2018
影响因子：
4
通讯作者：
Corson,TimothyW
中科院分区：
文献类型：
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作者：
Sulaiman,RaniaS;Park,Bomina;SheikPranBabu,SardarPasha;Si,Yubing;Kharwadkar,Rakshin;Mitter,SayakK;Lee,Bit;Sun,Wei;Qi,Xiaoping;Boulton,MichaelE;Meroueh,SamyO;Fei,Xiang;Seo,Seung-Yong;Corson,TimothyW
用于治疗眼部新生血管疾病如湿性年龄相关性黄斑变性（AMD）的标准护理疗法是靶向血管内皮生长因子信号传导的生物制剂。目前没有FDA批准的小分子用于治疗这些致盲性眼病。因此，具有新机制的治疗剂对于补充现有方法或与现有方法联合收割机组合至关重要。在这里，我们确定了可溶性环氧化物水解酶（sEH），环氧脂肪酸代谢的关键酶，作为一个目标的抗血管生成的同源异型，SH-11037。SH-11037在体外和体内抑制sEH，并与sEH水解酶结构域的底物结合裂缝对接。在脉络膜新生血管形成（CNV）小鼠模型的眼中，sEH水平和活性上调。sEH在人湿性AMD眼中过表达，提示sEH与新生血管形成有关。已知的sEH抑制剂递送眼内抑制的CNV。因此，通过剖析生物活性化合物的机制，我们鉴定了用于sEH抑制的新的化学型，并将sEH表征为阻断作为湿性AMD基础的CNV的靶标。
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 sEHin vitroandin vivoand 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.