The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IκB kinase Original Research Article

Abstract Background: Biologically active natural products continue to be useful in the exploration and control of intracellular signaling processes. For example, the sesquiterpene lactone parthenolide from the anti-inflammatory medicinal herb Feverfew (Tanacetum parthenium) appears to inhibit the pro-inflammatory signaling pathway. Parthenolide’s direct molecular target, however, remains unknown. We set out to identify the molecular mechanisms of parthenolide’s anti-inflammatory activity. Results: A parthenolide affinity reagent was synthesized and shown to bind directly to and inhibit IκB kinase β (IKKβ), the kinase subunit known to play a critical role in cytokine-mediated signaling. Mutation of cysteine 179 in the activation loop of IKKβ abolished sensitivity towards parthenolide. Moreover, we showed that parthenolide’s in vitro and in vivo anti-inflammatory activity is mediated through the α-methylene γ-lactone moiety shared by other sesquiterpene lactone