Structure‐based derivation and optimization of YAP‐like coactivator‐derived peptides to selectively target TEAD family transcription factors by hydrocarbon stapling and cyclization

Abstract Human transcriptional enhanced associate domain (TEAD) family consists of four paralogous transcription factors that function to modulate gene expression by interacting with YAP‐like coactivators and have been recognized as potential therapeutic targets of diverse diseases including lung cancer and gastric tumor. Here, we attempt to explore the systematic interaction profile between the 4 TEAD proteins and the peptides derived from the binding sites of 8 known YAP‐like coactivators, in order to analyze the binding affinity and recognition specificity of these peptides toward the TEAD family, and to design hydrocarbon‐stapled/cyclized peptides that can target the specific interaction profile for each coactivator. Structural, energetic, and dynamic investigations of TEAD–coactivator interactions reveal that the coactivators adopt three independent secondary structure regions (β‐strand, α‐helix, and Ω‐loop) to surround on the surface of TEAD proteins, in which the α‐helical and Ω‐loop regions are primarily responsible for the interactions. Five α‐helical peptides and four Ω‐loop peptides are derived from the 8 YAP‐like coactivators, and their systematic binding profile toward the 4 TEAD proteins is created, and hydrocarbon stapling and cyclization strategies are employed to constrain the free α‐helical and Ω‐loop peptides into their native conformations, respectively, thus effectively promoting peptide binding to TEADs. The all‐hydrocarbon and disulfide bridges are designed to point out the TEAD–peptide complex interface, which would not disrupt the direct intermolecular interaction between the TEAD and peptide. Therefore, the stapling and cyclization only improve peptide binding affinity to these TEADs, but do not alter peptide recognition specificity over different TEADs.