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J. Biol. Chem., Vol. 281, Issue 30, 21345-21352, July 28, 2006

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Peptide Aptamer-mediated Inhibition of Target Proteins by Sequestration into Aggresomes^*

Evangelia Tomai¹², Karin Butz¹, Claudia Lohrey, Fritz von Weizsäcker³, Hanswalter Zentgraf^¶, and Felix Hoppe-Seyler⁴

From the Molecular Therapy of Virus-Associated Cancers Group (F065) and the ^¶Electron Microcopy Group (F090), German Cancer Research Center, D-69120 Heidelberg, Germany and the Medizinische Universitätsklinik II, D-79106 Freiburg, Germany

Peptide aptamers (PAs) can be employed to block the intracellular function of target proteins. Little is known about the mechanism of PA-mediated protein inhibition. Here, we generated PAs that specifically bound to the duck hepatitis B virus (HBV) core protein. Among them, PA34 strongly blocked duck HBV replication by inhibiting viral capsid formation. We found that PA34 led to a dramatic intracellular redistribution of its target protein into perinuclear inclusion bodies, which exhibit the typical characteristics of aggresomes. As a result, the core protein is efficiently removed from the viral life cycle. Corresponding findings were obtained for bioactive PAs that bind to the HBV core protein or to the human papillomavirus-16 (HPV16) E6 protein, respectively. The observation that PAs induce the specific sequestration of bound proteins into aggresomes defines a novel mechanism as to how this new class of intracellular inhibitors blocks the function of their target proteins.

Received for publication, May 4, 2006 , and in revised form, May 22, 2006.

^* This work was supported in part by Grant 10-1930-Ho 5 from the Deutsche Krebshilfe. 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.

¹ Both authors have contributed equally to the work.

² Supported by the National Sciences and Engineering Research Council of Canada.

³ Present address: Department of Internal Medicine, Schlosspark Klinik, Heubnerweg 2, D-14059 Berlin, Germany.

⁴ To whom correspondence should be addressed: Deutsches Krebsfors-chungszentrum, F065, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany. Tel.: 49-6221-424872; Fax: 49-6221-424852; E-mail: hoppe-seyler{at}dkfz.de.

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