Cucurbitacin covalent bonding to cysteine thiols: the filamentous-actin severing protein Cofilin1 as an exemplary target.
BACKGROUND
Cucurbitacins are a class of triterpenoid natural compounds with potent bioactivities that led to their use as traditional remedies, and which continue to attract considerable attention as chemical biology tools and potential therapeutics. One obvious target is the actin-cytoskeleton; treatment with cucurbitacins results in cytoskeletal rearrangements that impact upon motility and cell morphology.


RESULTS
Cucurbitacin reacted with protein cysteine thiols as well as dithiothreitol, and we propose that the cucurbitacin mechanism of action is through broad protein thiol modifications that could result in inhibition of numerous protein targets. An example of such a target protein is Cofilin1, whose filamentous actin severing activity is inhibited by cucurbitacin conjugation.


CONCLUSIONS
The implications of these results are that cucurbitacins are unlikely to be improved for selectivity by medicinal chemistry and that their use as chemical biology probes to analyse the role of specific signalling pathways should be undertaken with caution.
Beatson Institute for Cancer Research, Garscube Estate, Switchback Road Glasgow G61 1BD, UK.
Mads
M
Gabrielsen
Maike
M
Schuldt
June
J
Munro
Dagmara
D
Borucka
Jenifer
J
Cameron
Mark
M
Baugh
Andrzej
A
Mleczak
Sergio
S
Lilla
Nicholas
N
Morrice
Michael F
MF
Olson
D008841:Actin Cytoskeleton / Q000378:metabolism; D051338:Cofilin 1 / Q000378:metabolism*; D054728:Cucurbitacins / Q000494:pharmacology*; D003545:Cysteine / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D011485:Protein Binding
C495810:CFL1 protein, human; D051338:Cofilin 1; D054728:Cucurbitacins; D003545:Cysteine