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Cucurbitacin covalent bonding to cysteine thiols: the filamentous-actin severing protein Cofilin1 as an exemplary target

Mads Gabrielsen1, Maike Schuldt1, June Munro1, Dagmara Borucka1, Jenifer Cameron1, Mark Baugh1, Andrzej Mleczak2, Sergio Lilla1, Nicholas Morrice1 and Michael F Olson1*

Author Affiliations

1 Beatson Institute for Cancer Research, Garscube Estate, Switchback Road Glasgow G61 1BD, UK

2 Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany

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Cell Communication and Signaling 2013, 11:58  doi:10.1186/1478-811X-11-58

Published: 14 August 2013



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.


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.


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.

Actin; Cofilin; Cytoskeleton; Cucurbitacin