Stapled peptide inhibitors target VGLL4/TEAD4 interactions to accelerate cutaneous wound healing.

Cutaneous wound healing is a crucial biological process for tissue repair, with skin fibroblasts acting as key cellular mediators in this regenerative cascade. The TEAD family, a downstream effector of the Hippo signaling pathway, plays a crucial role in maintaining tissue homeostasis, regulating cell proliferation, and promoting organ growth. Inhibiting TEAD4-VGLL4 interactions can initiate tissue repair and regeneration. Peptides have been created to modulate PPIs with varying success. In particular, stapling peptides can improve their ability to penetrate cell membranes and their stability, showing high specificity and activity compared to linear peptides, which highlights their broad potential in drug development. Based on the crystal structure of the VGLL4-mTEAD4 complex, we designed and synthesized a series of stapled peptides derived from the key motif of the VGLL4 protein. Among these peptides, the stapled peptides SHip2-5 and SHip2-6 effectively bind to the mTEAD4 protein, promote the proliferation and migration of skin fibroblasts, upregulate the expression levels of YAP and its downstream target genes, and present high α-helical content, stability, and membrane permeability. Moreover, SHip2-5 and SHip2-6 promote skin wound healing in rats. As novel VGLL4-mTEAD4 stapled peptide inhibitors, SHip2-5 and SHip2-6 serve as lead compounds for effective skin wound treatment, providing a new perspective and theoretical basis for the functional regeneration of damaged skin tissues. It also demonstrates strong potential for application and significant research value.