Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• RAS oncoproteins, particularly KRAS, are crucial regulators of cell signaling pathways.
• Mutations in KRAS are implicated in numerous aggressive cancers, making it a significant therapeutic target.

Purpose of the Study:

• To design and characterize a novel peptide-based inhibitor for KRAS.
• To investigate a metal-nucleated, switchable binding mechanism for KRAS inhibition.

Main Methods:

• Design of a bis-histidine peptide mimicking the SOS1 cofactor's αH helix.
• Coordination of the peptide with Palladium (Pd(II)) to create a metallopeptide binder.
• Utilized NMR spectroscopy and molecular dynamics (MD) for structural and binding studies.
• Assessed cellular internalization and inhibition of the MAPK signaling cascade in vitro.

Main Results:

• The Pd(II)-coordinated peptide exhibits high-affinity binding to KRAS.
• Pd(II) acts as a nucleator, promoting the peptide's bioactive α-helical conformation.
• The binding is switchable, reversible by addition or removal of Pd(II) via chelators.
• The metallopeptide effectively enters cells and inhibits the MAPK kinase cascade.

Conclusions:

• A novel, switchable Pd(II)-nucleated peptide binder for KRAS has been developed.
• This system demonstrates a metal-facilitated folding-upon-binding mechanism.
• The metallopeptide shows potential as a therapeutic agent for KRAS-driven cancers by inhibiting downstream signaling.