Chirality-driven folding of short β-lactam pseudopeptides

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Structural Biology

Background:

• Peptide-based drug design is limited by conformational flexibility and proteolytic degradation.
• β-lactam scaffolds offer a rigid alternative for creating peptide mimetics with enhanced stability.
• Understanding the conformational preferences of these novel scaffolds is crucial for their application.

Purpose of the Study:

• To synthesize novel enantiopure pseudopeptide models incorporating a central -(β-lactam)-(Aa)- scaffold.
• To investigate the conformational behavior of these pseudopeptides in solution and solid-state.
• To elucidate the influence of stereochemistry on the conformational equilibrium and chiral effects.

Main Methods:

• Synthesis of pseudopeptides from α-alkyl serines.
• 1D and 2D Nuclear Magnetic Resonance (NMR) spectroscopy for conformational analysis in solution.
• X-ray crystallography for solid-state structure determination.
• Computational chemistry (B3LYP/6-31++G**) for stability estimations.

Main Results:

• Successful synthesis of enantiopure pseudopeptides with a central -(β-lactam)-(Aa)- scaffold.
• NMR studies revealed an equilibrium between β-II and γ-turn conformers, modulated by residue configuration.
• Long-range chiral effects were observed, with specific residue arrangements stabilizing distinct turn motifs (β-II, β-II/β-I double turn).
• X-ray crystallography confirmed β-turned and open structures consistent with solution data.
• No β-hairpin nucleation was detected.

Conclusions:

• The synthesized β-lactam pseudopeptides exhibit distinct conformational preferences, primarily β-II and γ-turns.
• The relative configuration of residues significantly modulates the conformational equilibrium and chiral effects.
• A model explaining chiral influences based on steric interactions around the -(β-lactam)-(i + 2)- segment was proposed.
• These findings provide a foundation for designing conformationally constrained peptide mimetics.