Water-soluble β-strand peptidomimetics

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Design

Background:

• Protein-protein interactions (PPIs) are crucial in cellular processes and disease pathogenesis.
• Targeting PPIs is a challenging but promising therapeutic strategy.
• Non-peptidic scaffolds offer advantages over peptides for modulating PPIs.

Purpose of the Study:

• To develop novel non-peptidic scaffolds that mimic the side-chain display of beta-strands.
• To create conformationally preorganized molecules for potent and selective binding to protein targets.
• To demonstrate the synthetic feasibility and versatility of the scaffold design.

Main Methods:

• Rational design of scaffolds incorporating alternating (hetero)aromatic and cyclic urea units.
• Synthesis of beta-strand mimetics with diverse side-chain mimics (hydrophobic and hydrophilic).
• Conformational analysis and assessment of solubility in aqueous media.

Main Results:

• Demonstrated sequence diversity through incorporation of various side-chain mimics.
• Developed an improved synthetic route for scaffold generation.
• Confirmed conformational preorganization suitable for target binding in aqueous buffer.
• Scaffolds exhibit good solubility for further elaboration and deployment.

Conclusions:

• The developed non-peptidic scaffolds effectively mimic beta-strand structure and side-chain presentation.
• These scaffolds are suitable for modulating protein-protein interactions therapeutically.
• The approach is amenable to further optimization for specific protein targets.