Construction of Conformationally Constrained Lasso Peptides Targeting the YAP/TEAD interaction

Abstract

The Vestigial-like family member 4 (VGLL4) is a competitive inhibitor to the oncoprotein Yes-Associated Protein (YAP), that prevents the interaction of YAP to the transcription factor TEAD4. Given the well-documented role of YAP-TEAD4 interaction in gastric and colorectal cancer tumorigenesis, this work aimed to target TEAD4 by exploiting the inhibitory effects of VGLL4. The interest in a targeted, peptide-based therapy against these two cancers has recently grown, yet proteolytic degradation remains a key limitation of possible therapies. Highly stable, protease-resistant lasso peptides provide a possible “scaffold” in which bioactive sequences can be grafted. Previous work validated the potential to graft sequences into the lasso peptide astexin-1 that would tolerate alterations in its sequence. Here, I introduce the TDU2 domain of VGLL4, ITGSVDDHFAKALGDTWLQIKAA, into the disulfide-constrained tail of astexin-1. I show that the resulting fusion peptide did not bind robustly to TEAD4. Though further investigation of the binding reaction is required, the potential for lasso peptides to be used as peptide delivery vehicles to target oncoproteins remains.