Structure-guided discovery and evaluation of an EGFR L858R-targeting peptide with antiproliferative activity against ovarian cancer cells

EGFR L858R is an activating mutation associated with aberrant EGFR signalling, and molecules capable of recognising this mutant remain of research interest. In this study, a virtual peptide library containing 59 319 heptapeptides was screened against the EGFR L858R crystal structure, leading to the identification of four peptides with favourable predicted binding ability. Among them, Peptide-1 showed the strongest binding affinity in MST assays (Kd = 0.35 ± 0.02 μM), with higher affinity than the reference peptide DTP-1. Integrated structural and dynamic analyses showed that Peptide-1 could form a relatively stable binding conformation with EGFR L858R. Peptide-1 reduced the viability of SKOV3, OVCAR3, and CaOV3 cells, showed weaker effects on IOSE-80 cells, and its activity was markedly attenuated after EGFR-targeting shRNA transduction. In addition, Peptide-1 decreased Cyclin D1 mRNA expression and increased Caspase-3 mRNA expression. These findings indicate that Peptide-1 can be further investigated as an EGFR L858R-targeting peptide.