Euodenine A: A Small-Molecule Agonist of Human TLR4
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- 作者：Juliette E. Neve ; Hasanthi P. Wijesekera ; Sandra Duffy ; Ian D. Jenkins ; Justin A. Ripper ; Simon J. Teague ; Marc Campitelli ; Agatha Garavelas ; George Nikolakopoulos ; Phuc V. Le ; Priscila de A. Leone ; Ngoc B. Pham ; Philip Shelton ; Neil Fraser ; Anthony R. Carroll ; Vicky M. Avery ; Christopher McCrae ; Nicola Williams ; Ronald J. Quinn
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：February 27, 2014
- 年：2014
- 卷：57
- 期：4
- 页码：1252-1275
- 全文大小：790K
- 年卷期：v.57,no.4(February 27, 2014)
- ISSN：1520-4804
文摘
A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-魏B reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-伪, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage.