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Background <p>Previous studies have highlighted the critical role of the Yes associated protein 1 – TEA domain transcription factor (YAP1-TEAD) interaction in the progression of oral cancer. However, there remains a lack of direct disruptors targeting the YAP1-TEAD protein interaction and a detailed investigation of their effects on oral cancer. Therefore, we aimed to rationally design peptide YAP1-TEAD protein interaction disruptors through computational methods and explore the effects of direct disruption of the YAP1-TEAD interaction in oral squamous cell carcinoma (OSCC).</p> Methods <p>Peptide-based computational residue scanning was employed to design peptide disruptors of YAP1-TEAD interaction by analyzing the effects of mutations on binding affinity and stability. Molecular dynamics (MD) simulations were performed to assess the binding affinity and stability from a dynamic perspective. Surface plasmon resonance (SPR) assays were used to assess the in vitro binding affinities. After three rounds of iterative optimization, two with the highest affinities of this series of disruptors were applied to OSCC cell lines to investigate the primary effects of direct disruption of the YAP1-TEAD interaction.</p> Results <p>The expression of YAP1, TEADs, and four downstream transcriptional targets were significantly higher in OSCC tissues compared to paired normal tissues. The design and evaluation of YAP1-TEAD disruptors were conducted using computational residue scanning, MD simulations, and SPR assays. After three rounds of optimization, YTPD9 and YTPD11 demonstrated the highest affinities, with binding affinities 10 times more than that of the wildtype YAP1. When applied to OSCC cell lines, the disruptors exhibited a limited effect on cell proliferation, but they were able to inhibit the abilities of migration and invasion effectively.</p> Conclusion <p>This study developed a series of peptide disruptors targeting YAP1-TEAD protein interaction through computational simulations and in vitro experiments. The biological evaluation of two of these disruptors in OSCC confirmed that direct disruption of the YAP1-TEAD primarily affects the migration and invasion ability of oral cancer.</p>

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Design and biological evaluation of peptide disruptors targeting YAP1-TEAD interaction for oral cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Yue Wu,
  • Hao Yang,
  • Xianglei Zhang,
  • Lu Liu,
  • Yu Liu,
  • Chao Xu,
  • Kailiu Wu,
  • Guanying Feng,
  • Weijia Xu,
  • Xi Yang,
  • Chenping Zhang

摘要

Background

Previous studies have highlighted the critical role of the Yes associated protein 1 – TEA domain transcription factor (YAP1-TEAD) interaction in the progression of oral cancer. However, there remains a lack of direct disruptors targeting the YAP1-TEAD protein interaction and a detailed investigation of their effects on oral cancer. Therefore, we aimed to rationally design peptide YAP1-TEAD protein interaction disruptors through computational methods and explore the effects of direct disruption of the YAP1-TEAD interaction in oral squamous cell carcinoma (OSCC).

Methods

Peptide-based computational residue scanning was employed to design peptide disruptors of YAP1-TEAD interaction by analyzing the effects of mutations on binding affinity and stability. Molecular dynamics (MD) simulations were performed to assess the binding affinity and stability from a dynamic perspective. Surface plasmon resonance (SPR) assays were used to assess the in vitro binding affinities. After three rounds of iterative optimization, two with the highest affinities of this series of disruptors were applied to OSCC cell lines to investigate the primary effects of direct disruption of the YAP1-TEAD interaction.

Results

The expression of YAP1, TEADs, and four downstream transcriptional targets were significantly higher in OSCC tissues compared to paired normal tissues. The design and evaluation of YAP1-TEAD disruptors were conducted using computational residue scanning, MD simulations, and SPR assays. After three rounds of optimization, YTPD9 and YTPD11 demonstrated the highest affinities, with binding affinities 10 times more than that of the wildtype YAP1. When applied to OSCC cell lines, the disruptors exhibited a limited effect on cell proliferation, but they were able to inhibit the abilities of migration and invasion effectively.

Conclusion

This study developed a series of peptide disruptors targeting YAP1-TEAD protein interaction through computational simulations and in vitro experiments. The biological evaluation of two of these disruptors in OSCC confirmed that direct disruption of the YAP1-TEAD primarily affects the migration and invasion ability of oral cancer.