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Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent
Tomohisa Horibe1, Masayuki Kohno, Mari Haramoto
1Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyo-ku, Kyoto, 606-8501, Japan.
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.
Insights
A novel peptide targeting heat shock protein 90 (Hsp90) effectively kills various cancer cells while sparing normal cells. This Hsp90 inhibitor shows significant antitumor activity in preclinical models, offering a promising new cancer therapy.
Area of Science:
- Molecular biology
- Oncology
- Drug discovery
Background:
- Cancer treatment remains largely unchanged despite advances in molecular biology.
- Current therapies often lack specificity, harming normal cells alongside tumor cells.
- Heat shock protein 90 (Hsp90) is crucial for cancer cell survival and proliferation, making it a key therapeutic target.
Purpose of the Study:
- To develop a targeted therapy against Hsp90.
- To investigate the potential of a novel peptidomimetic inhibitor of Hsp90.
Main Methods:
- Engineered a cell-permeable peptidomimetic, the hybrid Antp-TPR peptide.
- Modeled the peptide on the Hsp90-p60/Hop binding interface.
- Tested the peptide's efficacy in vitro against various cancer cell lines and in vivo using a pancreatic cancer xenograft model.
Main Results:
- The hybrid Antp-TPR peptide selectively inhibited Hsp90-p60/Hop interaction.
- Induces cell death in breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines.
- Demonstrated significant antitumor activity in vivo without affecting normal cell viability.
Conclusions:
- The Antp-TPR peptide is a potent and selective anticancer agent.
- This Hsp90-targeting peptide represents a promising therapeutic strategy for cancer patients.
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