Targeted peptide-Au cluster binds to epidermal growth factor receptor (EGFR) in both active and inactive states: a clue for cancer inhibition through dual pathways

The epidermal growth factor receptor (EGFR) has become an important target protein in anticancer drug development. Meanwhile, peptide-Au cluster has been proposed as potential targeted nano-drug assembled by targeting peptide. Here, we designed and synthesized a novel peptide-Au cluster as Au₁₀Peptide₅ to target to EGFR. We found Au₁₀Peptide₅ could target to the natural binding sites of all EGFRs at membrane in both active and inactive states by molecular simulations. Its targeted ability was further verified by the co-localization and blocking experiments. We also study the configuration modifications of both active and inactive EGFRs after binding by Au₁₀Peptide₅. For active EGFR, the absorbed Au₁₀Peptide₅ might replace the natural ligand in EGFR endocytosis process. Then, the peptide-Au cluster in endochylema could inhibit the cancer relating enzyme activity including thioredoxin reductase1 (TrxR1) and induce the oxidative stress mediated apoptosis in tumor cells. For inactive EGFR, it was retained in inactive state by Au₁₀Peptide₅ binding to inhibit dimerization of EGFR for anticancer. Both pathways might be applied in anticancer drug development based on the theoretical and experimental study here.