2. Academic Validation
  3. Optical Control of Leukotriene A4 Hydrolase Using Photoswitchable Inhibitors

Optical Control of Leukotriene A4 Hydrolase Using Photoswitchable Inhibitors

  • J Med Chem. 2025 Oct 23;68(20):21520-21533. doi: 10.1021/acs.jmedchem.5c01654.
Xin Zhou 1,  Shumei Wang 1,  Xingye Yang 1 2,  Xin Zhang 1,  Zhao Ma 1,  Lupei Du 1,  Minyong Li 1 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Pharmaceutical College, Guangxi Key Laboratory of Pharmaceutical Precision Detection and Screening, Key Laboratory of Micro-Nanoscale Bioanalysis and Drug Screening of Guangxi Education Department, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China.
  • 3 Key Laboratory of Tropical Biological Resources (MOE), School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan 570228, China.
PMID: 41041960 DOI: 10.1021/acs.jmedchem.5c01654
Abstract

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.

Figures
Products