EGFRp4 Peptides: A Novel Strategy for Epidermal Growth Factor Receptor (EGFR) Inhibitor

The epidermal growth factor receptor (EGFR) plays a pivotal role in cell signaling pathways, and its malfunction is implicated in cancers such as lung, breast, and gastric cancer. Numerous studies have explored EGFR-specific peptides using various methods, excluding ribosome display peptide libraries. In this study, EGFRp1 and EGFRp4 peptides (11-mer) were discovered through ribosome display selection against the extracellular domain of EGFR (EGFR ECD or sEGFR). Notably, EGFRp4 exhibited superior binding affinity within the nanomolar range compared with other reported EGFR-specific peptides. It also demonstrated a positive cooperativity model with EGFR ECD across three experimental approaches: fluorescence polarization, surface plasmon resonance, and ligand tracer. Molecular docking substantiated this model, indicating that EGFRp4 prefers binding to active sEGFR conformations rather than inactive conformations. Furthermore, conjugating EGFRp4 onto NP1 using a GFLG linker notably enhanced the NP1 cyclic peptide performance in inhibiting EGFR-expressing cell lines. This conjugate demonstrated efficacy in inducing apoptosis and suppressing EGFR phosphorylation, comparable to that of Erlotinib. These findings underscore the potential of EGFRp4 as a peptide conjugate for EGFR-targeted applications.