Optical Control of Leukotriene A4 Hydrolase Using Photoswitchable Inhibitors

Leukotriene A4 hydrolase (LTA4H) is a prominent therapeutic target for leukotriene-associated inflammatory diseases, including cardiovascular diseases, asthma, and various tumor types. Using light to modulate LTA4H activity precisely is a leading approach to intervening in these inflammatory diseases. In this study, we utilized the azobenzene moiety to replace the diphenyl ether scaffold in LYS006, an LTA4H inhibitor developed by Novartis. We synthesized ten azobenzene-based photoswitchable LTA4H inhibitors with suitable photochemical properties. According to the enzymatic inhibitory assay, piLTA4H-1 was screened out since it significantly increases (∼150-fold) in inhibiting LTA4H when the condition changes from dark to 365 nm light exposure. Photoswitchable piLTA4H-1 could effectively modulate the eicosanoid release in mouse whole blood and enable the smart and effective intervention of arachidonic acid-induced ear dermatitis in mice. Optical control of LTA4H with piLTA4H-1 represents a promising strategy for inflammation intervention both in vitro and in vivo.白三烯A4水解酶（Leukotriene A4 hydrolase, LTA4H）是白三烯相关炎症性疾病的关键治疗靶点，此类疾病包括心血管疾病、哮喘及多种肿瘤亚型。通过光精准调控LTA4H活性，是干预此类炎症性疾病的主流研究方向。本研究采用偶氮苯基团替换诺华（Novartis）开发的LTA4H抑制剂LYS006中的二苯醚骨架，合成了10种具备适宜光化学特性的偶氮苯类光开关型LTA4H抑制剂。经酶抑制活性实验筛选，piLTA4H-1被证实为最优候选化合物：当环境从黑暗切换至365 nm光照条件时，其对LTA4H的抑制活性提升约150倍，效果显著。光控型抑制剂piLTA4H-1可有效调控小鼠全血中的类二十烷酸释放，并能够实现对花生四烯酸诱导的小鼠耳部皮炎的智能、高效干预。借助piLTA4H-1实现LTA4H的光学调控，为体外及体内炎症干预提供了一种极具应用前景的策略。