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.