Virtual screening and experimental validation of a METTL3-targeting peptide with in vitro antiproliferative activity against non-small cell lung cancer cells.

The METTL3-METTL14 protein-protein interaction (PPI) plays an important role in tumour progression, and disruption of this interaction has been explored as a potential strategy. In this study, four peptides were identified from a peptide database through virtual screening and molecular docking. Among them, peptide-1 showed the lowest Kd value among the tested peptides in MST analysis (Kd = 0.76 ± 0.02 μM). Binding mode analysis, molecular dynamics simulations, and MM/PBSA calculations suggested that peptide-1 might form a binding-related conformation with METTL3 under the simulated conditions. In lung cancer cells, peptide-1 showed growth-inhibitory activity, whereas weaker effects were observed in BEAS-2B cells. Peptide-1 also reduced the METTL3-METTL14-associated NanoBRET signal, decreased cellular m6A levels and JUNB mRNA expression, and its antiproliferative effect was attenuated by METTL3 knockdown. These findings suggest that peptide-1 may represent a METTL3-targeting peptide candidate for further evaluation.