%0 Journal Article
%T Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent
%A Tomohisa Horibe
%A Masayuki Kohno
%A Mari Haramoto
%A Koji Ohara
%A Koji Kawakami
%J Journal of Translational Medicine
%D 2011
%I BioMed Central
%R 10.1186/1479-5876-9-8
%X We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.It was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines in vitro. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis in vivo revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice.These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.Heat-shock protein 90 (Hsp90) is a molecular chaperone [1] that participates in the quality control of protein folding. The mechanism of action of Hsp90 includes sequential ATPase cycles and the stepwise recruitment of cochaperones, including Hsp70, CDC37, p60/Hsp-organizing protein (Hop), and p23 [2,3]. In particular, Hsp90 and Hsp70 interact with numerous cofactors containing so-called tetratricopeptide repeat (TPR) domains. TPR domains are composed of loosely conserved 34-amino acid sequence motifs that are repeated between one and 16 times per domain. Originally identified in components of the anaphase-promoting complex [4,5], TPR domains are now known to mediate specific protein interactions in numerous cellular contexts [6-8]. Moreover, apart from serving mere anchoring functions, TPR domains of the chaperone cofactors Hip and p60/Hop also are able to regulate the ATPase activities of Hsp70 and Hsp90, respectively [9,10]. Each 34-amino acid motif forms a pair of antiparallel ¦Á-helices. These motifs are arranged in a tandem array into a superhelical structure that encloses a central groove. The TPR-domain-containing cofactors of the Hsp70/Hsp
%U http://www.translational-medicine.com/content/9/1/8