Secondary Structure Stabilization of Macrocyclic Antimicrobial Peptides via Cross-Link Swapping

Area of Science:

• Biochemistry
• Peptide Chemistry
• Structural Biology

Background:

• Lactam cross-links are known to stabilize helical structures in antimicrobial peptides.
• Stabilization of beta-sheet conformations using lactamization has not been previously achieved.

Purpose of the Study:

• To stabilize beta-sheet conformation in a short peptide analogue using lactam cross-links.
• To investigate the impact of lactam cross-linking on the antibacterial activity and proinflammatory potential of the peptide.

Main Methods:

• Design of lactam cross-linked peptides using molecular dynamics simulations and Markov state models.
• Synthesis and conformational analysis of the designed peptides.
• Assessment of antibacterial activity and induction of proinflammatory activity in macrophages.

Main Results:

• Lactam cross-linked peptides adopted stabilized beta-sheet conformations, consistent with simulations.
• The lactam cross-linked peptide showed enhanced broad-spectrum antibacterial activity compared to the parent peptide.
• The modified peptide exhibited a greater propensity to induce proinflammatory activity in macrophages.

Conclusions:

• Lactam cross-linking can effectively stabilize beta-sheet structures in peptides.
• This approach enhances antimicrobial activity and modulates immune responses.
• The combination of computational and experimental methods provides a paradigm for designing constrained beta-sheet peptides for therapeutic applications.