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Peptide Aptamers Targeting Mutant p53 Induce Apoptosis in Tumor Cells

¹ The National Laboratory CIB, and Dipartimento di Biochimica, Biofisica, e Chimica delle Macromolecole (BBCM), University of Trieste, ² SISSA, International School for Advanced Studies and Consiglio Nazionale delle Ricerche-National Institute for Physics of Matter-DEMOCRITOS Modeling Center for Research in Atomistic Simulation, and ³ Italian Institute of Technology, Trieste, Italy

Requests for reprints: Giannino Del Sal, The National Laboratory CIB, Area Science Park, Padriciano 99, 34012, Trieste, Italy. Phone: 39-040-398992; Fax: 39-040-398990; E-mail: delsal{at}lncib.it.

Key Words: peptide aptamers • mutant p53 • gain-of-function • apoptosis • computational modeling

Mutations in the p53 tumor suppressor gene frequently result in expression of p53 point mutants that accumulate in cancer cells and actively collaborate with tumor progression through the acquisition of novel properties. Interfering with mutant p53 functions may represent a valid alternative for blocking tumor growth and development of aggressive phenotypes. The interactions and activities of selected proteins can be specifically modulated by the binding of peptide aptamers (PA). In the present work, we isolated PAs able to interact more efficiently with p53 conformational mutants compared with wild-type p53. The interaction between mutant p53 and PAs was further characterized using molecular modeling. Transient expression of PAs was able to reduce the transactivation activity of mutant p53 and to induce apoptosis specifically in cells expressing mutant p53. These PAs could provide a potential strategy to inhibit the oncogenic functions of mutant p53 and improve mutant p53-targeted cancer therapies. [Cancer Res 2008;68(16):6550–8]