Báo cáo hóa học: Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành hóa học dành cho các bạn yêu hóa học tham khảo đề tài: Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent
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Báo cáo hóa học: " Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent"Horibe et al. Journal of Translational Medicine 2011, 9:8http://www.translational-medicine.com/content/9/1/8 RESEARCH Open AccessDesigned hybrid TPR peptide targeting Hsp90 asa novel anticancer agentTomohisa Horibe, Masayuki Kohno, Mari Haramoto, Koji Ohara, Koji Kawakami* Abstract Background: Despite an ever-improving understanding of the molecular biology of cancer, the treatment of most cancers has not changed dramatically in the past three decades and drugs that do not discriminate between tumor cells and normal tissues remain the mainstays of anticancer therapy. Since Hsp90 is typically involved in cell proliferation and survival, this is thought to play a key role in cancer, and Hsp90 has attracted considerable interest in recent years as a potential therapeutic target. Methods: 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. Results: 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. Conclusion: These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.Background respectively [9,10]. Each 34-amino acid motif forms a pair of antiparallel a-helices. These motifs are arrangedHeat-shock protein 90 (Hsp90) is a molecular chaperone in a tandem array into a superhelical structure that[1] that participates in the quality control of protein fold- encloses a central groove. The TPR-domain-containinging. The mechanism of action of Hsp90 includes sequen- cofactors of the Hsp70/Hsp90 multi-chaperone systemtial ATPase cycles and the stepwise recruitment of interact with the C-terminal domains of Hsp70 andcochaperones, including Hsp70, CDC37, p60/Hsp-orga- Hsp90 [11]. Studies involving deletion mutagenesis havenizing protein (Hop), and p23 [2,3]. In particular, Hsp90 suggested that the C-terminal sequence motif EEVD-and Hsp70 interact with numerous cofactors containing COOH, which is highly conserved in all Hsp70s andso-called tetratricopeptide repeat (TPR) domains. TPR Hsp90s of the eukaryotic cytosol, has an important roledomains are composed of loosely conserved 34-amino in TPR-mediated cofactor binding [12]. Hop serves as anacid sequence motifs that are repeated between one and adapter protein for Hsp70 and Hsp90 [13,14], optimizing16 times per domain. Originally identified in components their functional cooperation [15] without itself acting as aof the anaphase-promoting complex [4,5], TPR domains molecular chaperone [16], and contains three TPRare now known to mediate specific protein interactions domains, each comprising three TPR motifs [17]. Thein numerous cellular contexts [6-8]. Moreover, apart N-terminal TPR domain of Hop, TPR1, specifically recog-from serving mere anchoring functions, TPR domai ...