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.