β-Strand mimetic foldamers rigidified through dipolar repulsion.

Area of Science:

• Biochemistry and Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Protein-protein interactions (PPIs) are vital targets for therapeutics.
• Hot-spot regions on secondary structures, particularly alpha-helices, are key to PPIs.
• Mimicking alpha-helical interactions is successful, but beta-strand mimicry is underdeveloped.

Purpose of the Study:

• To develop a foldamer capable of mimicking protein beta-strand structures.
• To investigate the conformational stability and determinants of this beta-strand mimic.

Main Methods:

• Design of a novel foldamer incorporating dipolar repulsion as a conformational determinant.
• Computational modeling to predict and analyze foldamer conformation.
• Solution- and solid-phase experiments to validate computational findings.

Main Results:

• The designed foldamer predominantly adopts the desired beta-strand conformation.
• Dipolar repulsion was identified as a key factor driving conformational stability.
• Experimental data corroborated computational predictions, confirming the foldamer's conformational ensemble.

Conclusions:

• A novel foldamer effectively mimics beta-strand conformations.
• This approach offers a promising strategy for targeting PPIs involving beta-strands.
• The foldamer's conformational stability, driven by dipolar repulsion, is suitable for therapeutic development.