Euodenine A: A Small-Molecule Agonist of Human TLR4
Citations Over TimeTop 15% of 2014 papers
Abstract
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-κB 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-α, 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.
Related Papers
- → Interaction of extracellular calcium and magnesium in the regulation of cytosolic calcium and PTH release in dispersed bovine parathyroid cells(1984)26 cited
- Influence of extracellular ion concentration on the intracellular accumulation of adriamycin.(1998)
- → Comparative in vitro bioactivity of cyclosporine on the proliferation of cultured peripheral blood mononuclear cells (PBMC) in sarcoidosis patients (SP) and healthy controls (HC)(2004)
- Unexpected Relationship of Extracellular ATP with Intracellular Ca Concentration in HepG2 Cells(2019)
- → Antipyrylazo III Measurements of Extracellular Ca Depletion in Heart Muscle(1985)