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J. Biol. Chem., Vol. 280, Issue 14, 13793-13800, April 8, 2005

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Design of a Novel Class of Peptide Inhibitors of Cyclin-dependent Kinase/Cyclin Activation^*

Claire Gondeau, Sabine Gerbal-Chaloin¶, Paul Bello||, Gudrun Aldrian-Herrada, May C. Morris, and Gilles Divita**

From the Centre de Recherches de Biochimie Macromoléculaire, Department of Molecular Biophysics and Therapeutics, FRE-2593 CNRS, 1919 Route de Mende, 34293 Montpellier, France and ^||Stem Cell Sciences Limited, P. O. Box 8224, Monash University L. P. O., Clayton, Victoria 3168, Australia

Cyclin dependent kinases (CDKs) are key regulators of the cell cycle progression and therefore constitute excellent targets for the design of anticancer agents. Most of the inhibitors identified to date inhibit kinase activity by interfering with the ATP-binding site of CDKs. We recently proposed that the protein/protein interface and conformational changes required in the molecular mechanism of CDK2-cyclin A activation were potential targets for the design of specific inhibitors of cell cycle progression. To this aim, we have designed and characterized a small peptide, termed C4, derived from amino acids 285–306 in the 5 helix of cyclin A. We demonstrate that this peptide does not interfere with complex formation but forms stable complexes with CDK2-cyclin A. The C4 peptide significantly inhibits kinase activity of complexes harboring CDK2 in a competitive fashion with respect to substrates but does not behave as an ATP antagonist. Moreover, when coupled with the protein transduction domain of Tat, the C4 peptide blocks the proliferation of tumor cell lines, thereby constituting a potent lead for the development of specific CDK-cyclin inhibitors.

Received for publication, December 6, 2004 , and in revised form, January 11, 2005.

^* This work was supported in part by CNRS and grants from the French Association pour la Recherche contre le Cancer Grants ARC-4326 (to M. C. M.) and ARC-5271 (to G. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a grants from HMR-Aventis, Sidaction.

^¶ Supported by European Commission Grant QLK2-CT-2001-01451.

^** To whom correspondence should be addressed. Tel.: 33-04-6761-3392; Fax: 33-04-6752-1559; E-mail: gilles.divita{at}crbm.cnrs.fr.

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