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

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• 作者：Hu Meng ; Christopher L. McClendon ; Ziwei Dai ; Kenan Li ; Xiaoling Zhang ; Shan He ; Erchang Shang ; Ying Liu ; Luhua Lai
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 12, 2016
• 年：2016
• 卷：59
• 期：9
• 页码：4202-4209
• 全文大小：476K
• 年卷期：0
• ISSN：1520-4804

文摘

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.