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Discovery of Novel 15-Lipoxygenase Activators To Shift the Human Arachidonic Acid Metabolic Network toward Inflammation Resolution.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Meng H,McClendon CL,Dai Z,Li K,Zhang X,He S,Shang E,Liu Y,Lai L

doi

10.1021/acs.jmedchem.5b01011

subject

Has Abstract

pub_date

2016-05-12 00:00:00

pages

4202-9

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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