The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase
2001 (English)In: Chemistry & Biology, Vol. 8, no 8, 759-77 p.Article in journal (Refereed) Published
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 lactones.
Conclusions: In recent years, the multi-subunit IKK complex has been shown to be responsible for cytokine-mediated stimulation of genes involved in inflammation and as such represents an attractive target for pharmaceutical intervention. Our finding that parthenolide targets this kinase complex provides a possible molecular basis for the anti-inflammatory properties of parthenolide. In addition, these results may be useful in the development of additional anti-inflammatory agents.
Place, publisher, year, edition, pages
2001. Vol. 8, no 8, 759-77 p.
Parthenolide, Feverfew, IκB kinase, Anti-inflammatory
IdentifiersURN: urn:nbn:se:umu:diva-9120DOI: doi:10.1016/S1074-5521(01)00049-7OAI: oai:DiVA.org:umu-9120DiVA: diva2:148791