Abstract
KRAS is one of the most frequently mutated oncogenes in human cancers and remains a challenging target for therapeutic intervention, often labeled "undruggable." We herein synthesized triazole-containing peptidomimetics TTh1 and TTh2, to explore their selective interactions with DNA quadruplexes. Biophysical studies reveal that TTh2 with a prolinamide motif selectively binds to and stabilizes the KRAS G-quadruplex structure, resulting in marked suppression of the KRAS mRNA and protein levels in HeLa cells. This downregulation correlates with the inhibition of key downstream signaling pathways, including MAPK and Akt/mTOR, which are critical for cancer cell proliferation and survival. These results highlight the potential of G4-binding peptidomimetics as chemical tools for modulating oncogene expression through selective stabilization of promoter G-quadruplex structures.