Piptides: New, Easily Accessible Chemotypes For Interactions With Biomolecules

Area of Science:

• Biomolecular science
• Chemical biology
• Drug discovery

Background:

• Small molecule probes are essential tools in biomolecular science.
• Developing novel chemical entities for probe discovery is a key research area.
• Protein-protein interactions (PPIs) are important targets for therapeutic intervention.

Purpose of the Study:

• To develop a novel non-peptidic chemotype, termed piptides, suitable for solid-phase synthesis and probe discovery.
• To explore the utility of piptides in targeting protein-protein interactions.
• To evaluate piptides against the epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) interaction.

Main Methods:

• Solid-phase synthesis of a piptide library from pip acid building blocks.
• Utilizing the Exploring Key Orientations (EKO) strategy for candidate evaluation.
• Assessing piptide disruption of the EGF-EGFR interaction in vitro and in cell-based assays.

Main Results:

• A library of 14 piptides was synthesized and screened.
• Five piptide members demonstrated disruption of the EGF-EGFR interaction at low micromolar concentrations.
• These active piptides induced apoptotic cell death and antagonized EGF-induced EGFR phosphorylation.

Conclusions:

• Piptides represent a promising non-peptidic chemotype for biomolecular probe development.
• Piptides exhibit good stability and are amenable to efficient synthesis.
• Piptides targeting the EGF-EGFR interaction show potential for further therapeutic development.