Academic Journal
Development of a Double-Stapled Peptide Stabilizing Both α‑Helix and β‑Sheet Structures for Degrading Transcription Factor AR-V7
| العنوان: | Development of a Double-Stapled Peptide Stabilizing Both α‑Helix and β‑Sheet Structures for Degrading Transcription Factor AR-V7 |
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| المؤلفون: | Bohan Ma, Donghua Liu, Mengjun Zheng, Zhe Wang, Dize Zhang, Yanlin Jian, Jian Ma, Yizeng Fan, Yule Chen, Yang Gao, Jing Liu, Xiang Li, Lei Li |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | Biophysics, Biochemistry, Medicine, Pharmacology, Biotechnology, Computational Biology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, weak proteolytic resistance, molecular dynamics simulations, dna binding domain, class ” heterogeneous, shown limited applicability, limited membrane permeability, successfully stabilized α, based protac drugs, stapled peptide capable, specific peptide protac, poor conformational stability, sheet peptide motifs, stapled peptide stabilizing, α ‑ helix, limited stability, based protac, stapled peptide, simultaneously stabilizing, sheet structures, staple peptide, peptide stapling, conformational double |
| الوصف: | Peptide drugs offer distinct advantages in therapeutics; however, their limited stability and membrane penetration abilities hinder their widespread application. One strategy to overcome these challenges is the hydrocarbon peptide stapling technique, which addresses issues such as poor conformational stability, weak proteolytic resistance, and limited membrane permeability. Nonetheless, while peptide stapling has successfully stabilized α-helical peptides, it has shown limited applicability for most β-sheet peptide motifs. In this study, we present the design of a novel double-stapled peptide capable of simultaneously stabilizing both α-helix and β-sheet structures. Our designed double-stapled peptide, named DSARTC, specifically targets the androgen receptor (AR) DNA binding domain and MDM2 as E3 ligase. Serving as a peptide-based PROTAC (proteolysis-targeting chimera), DSARTC exhibits the ability to degrade both the full-length AR and AR-V7. Molecular dynamics simulations and circular dichroism analysis validate the successful constraint of both secondary structures, demonstrating that DSARTC is a “first-in-class” heterogeneous-conformational double-stapled peptide drug candidate. Compared to its linear counterpart, DSARTC displays enhanced stability and an improved cell penetration ability. In an enzalutamide-resistant prostate cancer animal model, DSARTC effectively inhibits tumor growth and reduces the levels of both AR and AR-V7 proteins. These results highlight the potential of DSARTC as a more potent and specific peptide PROTAC for AR-V7. Furthermore, our findings provide a promising strategy for expanding the design of staple peptide-based PROTAC drugs, targeting a wide range of “undruggable” transcription factors. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://figshare.com/articles/journal_contribution/Development_of_a_Double-Stapled_Peptide_Stabilizing_Both_Helix_and_Sheet_Structures_for_Degrading_Transcription_Factor_AR-V7/25104034 |
| DOI: | 10.1021/jacsau.3c00795.s001 |
| الاتاحة: | https://doi.org/10.1021/jacsau.3c00795.s001 https://figshare.com/articles/journal_contribution/Development_of_a_Double-Stapled_Peptide_Stabilizing_Both_Helix_and_Sheet_Structures_for_Degrading_Transcription_Factor_AR-V7/25104034 |
| Rights: | CC BY-NC 4.0 |
| رقم الانضمام: | edsbas.B2835D68 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/jacsau.3c00795.s001 |
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