Systematic profiling of all 4 TEAD proteins against 8 YAP-like coactivator peptides, followed by hydrocarbon stapling and cyclization, produced optimized peptides with improved TEAD binding while preserving selectivity across the family.
Selectivity preservedHydrocarbon stapling and cyclization improved peptide binding to TEADs without altering which specific TEAD each peptide targets — enabling precision cancer targeting
What the researchers found
Systematic binding profiles created for 9 peptides (5 α-helical, 4 Ω-loop) from 8 coactivators against all 4 TEADs. Hydrocarbon stapling and cyclization improved binding affinity without altering TEAD recognition specificity.
Why it matters
Different cancers involve different TEAD proteins. Having a library of optimized peptides targeting each TEAD specifically enables precision cancer therapy — matching the right peptide to the right tumor type.
The numbers in context
4 TEAD targets; 8 coactivator sources; 9 peptides (5 helical, 4 loop); stapling/cyclization improved affinity; selectivity unchanged
How the study worked
Computational structural, energetic, and dynamic investigations. Systematic TEAD-coactivator interaction profiling. Hydrocarbon stapling of α-helical peptides and disulfide cyclization of Ω-loop peptides. Binding affinity analysis.
Who was studied
In silico design and fluorescence polarization validation
What this study cannot tell us
Computational study with structural modeling — experimental binding validation needed. No cell-based or in vivo anti-cancer activity tested. Manufacturing multiple specialized peptides may be complex.
How to read the evidence
Low evidence grade: computational design study without experimental validation of anti-cancer activity. Important for drug design methodology.
When this study was published
Published 2021. TEAD-targeting for cancer continues to advance with pharmaceutical industry interest.
The bigger picture
This systematic approach to TEAD targeting exemplifies modern precision peptide drug design — creating a library of selective inhibitors rather than one-size-fits-all drugs. The methodology could be applied to other transcription factor families.
Questions still open
- Which TEAD-specific stapled peptide shows the greatest anti-tumor activity in cell-based assays?
- Can the most promising peptides be delivered into tumor cells effectively?
- Would TEAD-family-wide blockade or TEAD-specific inhibition be more effective clinically?
Common questions
Why do cancers need different peptide drugs?
What makes stapled peptides better than regular peptides?
Read the original research
Structure-based derivation and optimization of YAP-like coactivator-derived peptides to selectively target TEAD family transcription factors by hydrocarbon stapling and cyclization.
Chemical biology & drug design, 97(6), 1129-1136
Citation
He, Bo; Wu, Tao; He, Ping; Lv, Fenglin; Liu, Hongxiang. (2021). Structure-based derivation and optimization of YAP-like coactivator-derived peptides to selectively target TEAD family transcription factors by hydrocarbon stapling and cyclization.. Chemical biology & drug design, 97(6), 1129-1136. https://doi.org/10.1111/cbdd.13813