A Polyproline Type II Peptidomimetic Disrupts a Grb2 SH3C Domain Protein-Protein Interaction Implicated in Breast...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• Protein-protein interactions (PPIs) are crucial for cellular signaling and are key therapeutic targets.
• Mimicking protein secondary structures, like alpha-helices and beta-sheets, is a promising strategy for modulating PPIs.
• The interaction between Grb2 and Gab2's polyproline II (PPII) helix is critical for cell growth and proliferation in various cancers.

Purpose of the Study:

• To present the first general approach for nonpeptidic mimicry of extended PPII helices.
• To demonstrate a scaffold that can replicate the binding of Gab2's hot-spot side-chains.
• To validate the use of diverse secondary structure peptidomimetics in disrupting therapeutically relevant PPIs.

Main Methods:

• Rational design of a nonpeptidic scaffold to mimic PPII helices.
• Functionalization of the scaffold to recapitulate Gab2 hot-spot side-chain characteristics.
• Protein-observed nuclear magnetic resonance (NMR) to confirm binding site.
• Surface plasmon resonance (SPR) to determine binding affinities.

Main Results:

• A novel nonpeptidic scaffold successfully mimics extended PPII helices.
• The designed peptidomimetic binds to Grb2 at the same site as the native Gab2 peptide.
• Binding affinities of the peptidomimetic are comparable to the native peptide sequence.
• The scaffold can be functionalized to incorporate key hydrophobic and cationic interactions.

Conclusions:

• This study introduces a general strategy for nonpeptidic PPII helix mimicry.
• The developed peptidomimetic effectively disrupts the Grb2-Gab2 interaction, a target in cancer therapy.
• This work supports the broader application of diverse secondary structure peptidomimetics for targeting PPIs.