Discovery of Novel 15-Lipoxygenase Activators To Shift the Human Arachidonic Acid Metabolic Network toward Inflammation Resolution.
For disease network intervention, up-regulating enzyme activities is equally as important as down-regulating activities. However, the design of enzyme activators presents a challenging route for drug discovery. Previous studies have suggested that activating 15-lipoxygenase (15-LOX) is a promising strategy to intervene the arachidonic acid (AA) metabolite network and control inflammation. To prove this concept, we used a computational approach to discover a previously unknown allosteric site on 15-LOX. Both allosteric inhibitors and novel activators were discovered using this site. The influence of activating 15-LOX on the AA metabolite network was then investigated experimentally. The activator was found to increase levels of 15-LOX products and reduce production of pro-inflammatory mediators in human whole blood assays. These results demonstrate the promising therapeutic value of enzyme activators and aid in further development of activators of other proteins.
Hu
H
Meng
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego , La Jolla, California 92093, United States.
Christopher L
CL
McClendon
Ziwei
Z
Dai
Kenan
K
Li
Xiaoling
X
Zhang
Shan
S
He
Erchang
E
Shang
Ying
Y
Liu
Luhua
L
Lai
D000495:Allosteric Site; D001093:Arachidonate 15-Lipoxygenase / Q000187:drug effects*; D016718:Arachidonic Acid / Q000378:metabolism*; D002474:Cell-Free System; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D001093:Arachidonate 15-Lipoxygenase