Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide

Mutations to oncogenic protein KRAS are responsible for some of the deadliest cancers, and KRAS is thus a key target for new antitumour agents. Here, a short bis-histidine peptide derived from the alpha H helix of the cofactor SOS1 is designed and shown to reversibly bind to KRAS with high affinity upon coordination to Pd(II), inhibiting KRAS-activated pathways in live cells. RAS oncoproteins are molecular switches associated with critical signaling pathways that regulate cell proliferation and differentiation. Mutations in the RAS family, mainly in the KRAS isoform, are responsible for some of the deadliest cancers, which has made this protein a major target in biomedical research. Here we demonstrate that a designed bis-histidine peptide derived from the alpha H helix of the cofactor SOS1 binds to KRAS with high affinity upon coordination to Pd(II). NMR spectroscopy and MD studies demonstrate that Pd(II) has a nucleating effect that facilitates the access to the bioactive alpha-helical conformation. The binding can be suppressed by an external metal chelator and recovered again by the addition of more Pd(II), making this system the first switchable KRAS binder, and demonstrates that folding-upon-binding mechanisms can operate in metal-nucleated peptides. In vitro experiments show that the metallopeptide can efficiently internalize into living cells and inhibit the MAPK kinase cascade.

Automated summary

A short peptide was designed to reversibly bind to KRAS upon coordination to Pd(II), inhibiting its activated pathways in live cells. The peptide can efficiently internalize into cells and inhibit the MAPK kinase cascade.