1 research outputs found
Euodenine A: A Small-Molecule Agonist of Human TLR4
A small-molecule natural product,
euodenine A (<b>1</b>),
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. <b>1</b> 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 <b>1</b> could modulate the Th2 immune response without causing lung
damage