Design and biological evaluation of peptide disruptors targeting YAP1-TEAD interaction for oral cancer
Yue Wu1, Hao Yang2, Xianglei Zhang2
1Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
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.
Insights
We designed peptide disruptors to block the YAP1-TEAD interaction, crucial in oral cancer progression. These disruptors effectively inhibited oral squamous cell carcinoma (OSCC) cell migration and invasion, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- The Yes associated protein 1 - TEA domain transcription factor (YAP1-TEAD) interaction is implicated in oral cancer progression.
- A lack of direct YAP1-TEAD interaction disruptors and their specific effects in oral cancer necessitates further investigation.
Purpose of the Study:
- To rationally design peptide disruptors targeting the YAP1-TEAD protein interaction using computational methods.
- To explore the effects of directly disrupting the YAP1-TEAD interaction in oral squamous cell carcinoma (OSCC).
Main Methods:
- Peptide-based computational residue scanning was used to design YAP1-TEAD interaction disruptors.
- Molecular dynamics (MD) simulations and surface plasmon resonance (SPR) assays assessed binding affinity and stability.
- Developed disruptors were applied to OSCC cell lines to evaluate their biological effects.
Main Results:
- YAP1, TEADs, and downstream targets were upregulated in OSCC tissues.
- Two optimized peptide disruptors, YTPD9 and YTPD11, showed significantly higher binding affinities than wildtype YAP1.
- These disruptors limited OSCC cell proliferation but effectively inhibited migration and invasion.
Conclusions:
- A series of peptide disruptors targeting the YAP1-TEAD interaction were successfully developed using computational and in vitro methods.
- Direct disruption of the YAP1-TEAD interaction primarily impacts the migration and invasion capabilities of oral cancer cells.
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