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.