Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 9, Pages 4202-4209Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01011
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Funding
- Ministry of Science and Technology of China [2012AA020308, 2015CB910300]
- National Natural Science Foundation of China [21573012, 91313302, 21173013]
- East Asia and Pacific Summer Institutes (EAPSI) grant [OISE-1107560]
- NIH [GM099197-03]
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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.
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