Euodenine A: a small-molecule agonist of human TLR4.
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.
Eskitis Institute for Drug Discovery, Griffith University , Nathan, 4111 Queensland, Australia.
Juliette E
JE
Neve
Hasanthi P
HP
Wijesekera
Sandra
S
Duffy
Ian D
ID
Jenkins
Justin A
JA
Ripper
Simon J
SJ
Teague
Marc
M
Campitelli
Agatha
A
Garavelas
George
G
Nikolakopoulos
Phuc V
PV
Le
Priscila
P
de A Leone
Ngoc B
NB
Pham
Philip
P
Shelton
Neil
N
Fraser
Anthony R
AR
Carroll
Vicky M
VM
Avery
Christopher
C
McCrae
Nicola
N
Williams
Ronald J
RJ
Quinn
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D015363:Quinolones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000819:agonists*
C588086:1,10,10-trimethyl-2-(3,4,5-trimethoxyphenyl)-1,2,2a,4,10,10a-hexahydro-3H-cyclobuta(4,5)pyrano(3,2-c)quinolin-3-one; D016207:Cytokines; D006576:Heterocyclic Compounds, 4 or More Rings; D015363:Quinolones; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4