Light-Controlled Modulation of 15-Lipoxygenase-1 Regulates Intestinal Inflammatory Signaling

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Enzyme Inhibitor Design

Background:

• Photopharmacology enables spatiotemporal control of biological processes.
• Rational design of photoswitchable enzyme inhibitors is challenging.
• Human 15-lipoxygenase-1 (15-LOX-1) is implicated in inflammation, ferroptosis, and cancer.

Purpose of the Study:

• To develop a target-guided strategy for diazo-based photoswitchable inhibitors of 15-LOX-1.
• To create complementary photoswitch classes with distinct photo-switching behaviors.
• To validate 15-LOX-1 as a therapeutic target and demonstrate light-controlled inhibition in cellular and in vivo models.

Main Methods:

• Design and synthesis of reversible azobenzenes (ABs), azo-heteroarenes (HAs), and covalent azo-bis-alkynes (BAs).
• Characterization of photoisomerization, bistability, and inhibitory activity using enzymatic and kinetic studies.
• Validation in cellular and in vivo mouse models of colonic inflammation, including IL-8 expression analysis.

Main Results:

• Developed three classes of diazo-based photoswitchable inhibitors (ABs, HAs, BAs) with efficient E/Z photoisomerization and high bistability.
• AB and HA derivatives act as E-ON/Z-OFF inhibitors, while BA derivatives exhibit Z-ON/E-OFF behavior.
• Demonstrated photoisomer-dependent suppression of IL-8 in cellular and in vivo models of colonic inflammation, validating 15-LOX-1 as a therapeutic target.

Conclusions:

• Established a generalizable framework for rational development of selective photoswitchable inhibitors.
• Achieved programmable light-controlled modulation of 15-LOX-1 activity.
• Showcased the therapeutic potential of photoswitchable 15-LOX-1 inhibitors in inflammatory conditions.