Rational design and chemical modification of TEAD coactivator peptides to target hippo signaling pathway against gastrointestinal cancers

Gao, Shuxia; Wang, Yingchao; Ji, Lijuan

doi:10.1080/10799893.2020.1818093

Cited by 14 publications

(6 citation statements)

References 39 publications

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“…To this end, a new rational design methodology was recently proposed that employs a chemical modification, termed hydrocarbon stapling technique, to retain the conformation of the α‐helix peptide. This approach can improve peptide binding to TEAD and interfere effectively with coactivators‐transcription factor complex formation 21 …”

Section: Figurementioning

confidence: 99%

“…This approach can improve peptide binding to TEAD and interfere effectively with coactivatorstranscription factor complex formation. 21 YAP is also implicated in the angiogenic process of diverse solid tumours and small-molecule inhibitors targeting that aspect of YAP function have been developed. Verteporfin (VP) is a low-molecular mass compound that suppresses YAP signalling by hampering YAP/ TEAD interactions and can restrain proliferation, migration, tube formation and facilitate apoptosis of human umbilical vein endothelial cells (HUVECs).…”

mentioning

confidence: 99%

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Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics

Gargalionis

Papavassiliou

2023

J Cellular Molecular Medi

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Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics

Gargalionis

Papavassiliou

2023

J Cellular Molecular Medi

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“…Given most TEAD proteins are involved in gastrointestinal carcinoma such as esophageal and gastric cancers, 5 the TEAD4 was also reported to closely associate with the tumorigenesis of nasopharyngeal cancer (NPC) 6,7 . For example, the binding of YAP1 to TEAD4 was revealed to promote tumor invasion and metastasis in NPC with hepatitis virus infection, 8 which was also found to be responsible for cisplatin resistant‐induced epithelial‐mesenchymal transition 9 and ophiopogonin‐induced reactive oxygen species‐dependent apoptosis in NPC cells 10 .…”

Section: Introductionmentioning

confidence: 99%

“…3 Despite the high homology and expression pattern shared by them, evidences showed that the downstream partners and physiological functions of TEAD proteins are exquisitely different; each has tissue-specific roles, such as cardiogenesis, neural development, and trophectoderm lineage determination, during embryonic development. 4 Given most TEAD proteins are involved in gastrointestinal carcinoma such as esophageal and gastric cancers, 5 the TEAD4 was also reported to closely associate with the tumorigenesis of nasopharyngeal cancer (NPC). 6,7 For example, the binding of YAP1 to TEAD4 was revealed to promote tumor invasion and metastasis in NPC with hepatitis virus infection, 8 which was also found to be responsible for cisplatin resistant-induced epithelial-mesenchymal transition 9 and ophiopogonin-induced reactive oxygen species-dependent apoptosis in NPC cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular design and rational optimization of synergistic effect between the two wings of a roughly orthogonal cation‐π‐π stacking system at nasopharyngeal carcinoma YAP1‐TEAD4 parallel Helix‐Helix interaction interface

Zhu

et al. 2022

J of Molecular Recognition

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The Yes-associated protein-1 (YAP1) is an essential regulator of human Hippo signaling pathway and functions through interaction with TEA domain-4 (TEAD4) transcription factor involved in the tumorigenesis of nasopharyngeal cancer. Previously, a parallel helix-helix interaction (PHHI) was identified as the key hotspot at YAP1-TEAD4 complex interface and has been exploited as an attractive druggable target to disrupt the complex. In this study, we investigated a roughly orthogonal cation-π-π stacking system across the crystal PHHI packing interface by integrating computational modeling and binding assay, which forms between one YAP1 helical residue Phe69 and two TEAD4 helical residues Phe373/Lys376. A synergistic effect between cation-π and π-π interactions was observed; they separately represent two wings of the stacking system. The π-electron is primarily responsible for the synergistic effect. Combination between diverse aromatic/charged amino acids. as well as neutral alanine on the cation-π-π stacking, revealed that the presence of aromatic tryptophan and charged arginine at, respectively, the residues 373 and 376 of TEAD4 helix can considerably improve PHHI binding affinity by $6-fold, whereas neutral alanine substitution on each residue and on both would reduce the affinity significantly, confirming a strong synergistic effect involved in the roughly orthogonal cation-π-π stacking system at YAP1-TEAD4 PHHI interface.

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“…Besides the YAP, TAZ, and VGLLs, the FAM181A and FAM181B were also reported as the potential YAP‐like coactivators of TEADs, but the biological functions are not clear. Recent studies found that chemically restricted peptide segments derived from the functional regions of YAP and TAZ and VGLL4 can disrupt the Hippo pathway by directly targeting TEADs, which were exploited as a promising therapeutic strategy against a number of cancers such as lung cancer, gastric cancer, and esophageal cancer (Gao et al., 2020; Wu et al., 2020; Zhang et al., 2020).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

Chem Biol Drug Des

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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.

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Rational design and chemical modification of TEAD coactivator peptides to target hippo signaling pathway against gastrointestinal cancers

Cited by 14 publications

References 39 publications

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics

Molecular design and rational optimization of synergistic effect between the two wings of a roughly orthogonal cation‐π‐π stacking system at nasopharyngeal carcinoma YAP1‐TEAD4 parallel Helix‐Helix interaction interface

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

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