Celastrol: Molecular targets of Thunder God Vine.
Celastrol, a quinone methide triterpene, is a pharmacologically active compound present in Thunder God Vine root extracts used as a remedy of inflammatory and autoimmune diseases, e.g. rheumatoid arthritis. Celastrol is one of the most promising medicinal molecules isolated from the plant extracts of traditional medicines. Molecular studies have identified several molecular targets which are mostly centered on the inhibition of IKK-NF-kappaB signaling. Celastrol (i) inhibits directly the IKKalpha and beta kinases, (ii) inactivates the Cdc37 and p23 proteins which are co-chaperones of HSP90, (iii) inhibits the function of proteasomes, and (iv) activates the HSF1 and subsequently triggers the heat shock response. It seems that the quinone methide structure present in celastrol can react with the thiol groups of cysteine residues, forming covalent protein adducts. In laboratory experiments, celastrol has proved to be a potent inhibitor of inflammatory responses and cancer formation as well as alleviating diseases of proteostasis deficiency. Celastrol needs still to pass several hurdles, e.g. ADMET assays, before it can enter the armoury of western drugs.
Salminen
Antero
A
Department of Neurology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland. antero.salminen@uef.fi
Lehtonen
Marko
M
Paimela
Tuomas
T
Kaarniranta
Kai
K
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D015551:Autoimmunity / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D018833:Chaperonins / Q000037:antagonists & inhibitors; D003545:Cysteine / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000819:agonists; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry; D000071876:Prostaglandin-E Synthases; D014157:Transcription Factors / Q000819:agonists; D029757:Tripterygium / Q000737:chemistry*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts; D014157:Transcription Factors; D014315:Triterpenes; C496559:CHUK protein, human; D051550:I-kappa B Kinase; D018833:Chaperonins; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D003545:Cysteine; C050414:celastrol