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Intracellular targets of paullones : identification by affinity chromatography using immobilized inhibitor.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

  • Marie Knockaert
  • Karen Wieking
  • Sophie Schmitt
  • Maryse Leost
  • Karen M. Grant
  • Jeremy C. Mottram
  • Conrad Kunick
  • Laurent Meijer
<mark>Journal publication date</mark>12/07/2002
<mark>Journal</mark>Journal of Biological Chemistry
Issue number28
Number of pages9
Pages (from-to)25493-25501
Publication StatusPublished
<mark>Original language</mark>English


Numerous inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3 (GSK-3) are being developed in view of their potential applications against cancers and neurodegenerative disorders. Among these, paullones constitute a family of potent and apparently selective cyclin-dependent kinase and GSK-3 inhibitors. However, their actual intracellular targets remain to be identified. To address this issue we have immobilized a paullone, gwennpaullone, on an agarose matrix. Extracts from various cell types and tissues were screened for proteins interacting with this matrix. This approach validated GSK-3 and GSK-3 as major intracellular paullone targets and also mitochondrial, but not cytoplasmic, malate dehydrogenase (MDH). Mitochondrial MDH was indeed inhibited by micromolar concentrations of paullones. Mitochondrial MDH was the major paullone-binding protein in the parasitic protozoon Leishmania mexicana, and paullones inhibited growth of the parasite. This simple batchwise affinity chromatography approach constitutes a straightforward method for the identification of intracellular targets of this particular class of novel anti-mitotic compounds. It has revealed an unexpected target, mitochondrial MDH, the inhibition of which may participate in the pharmacological effects of paullones.