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<p>Understanding antimicrobial peptide (AMP) structural determinants is crucial for clinical development. While most designed AMPs are short and helical, many natural ones have unstructured or cyclic C-terminal tails with poorly defined functions. We studied mesco-2 from the flatworm <i>Mesocestoides corti</i>, with an N-terminal α-helix kinked around a palindromic GRGIGRG motif and an unstructured C-terminal tail containing a disulfide-forming CLGRC motif, along with its disulfide-reduced analogue mesco-2&#xa0;A. Similar CXXXC motifs are common in flatworm AMPs and typically occur in unstructured regions, as indicated by the sequence analysis. Molecular modelling revealed that the C-terminal disulfide loop modulates mesco-2 flexibility and oligomerization. Both peptides displayed strong antibacterial activity and low cytotoxicity. Differences appeared in their effect on bacterial growth kinetics at sub-bactericidal concentrations. Flow cytometry and fluorescence imaging confirmed membrane-related mechanisms, but for mesco-2&#xa0;A the membrane-disruptive effect was slower. Atomic force microscopy confirmed their distinct membrane interaction modes, and circular dichroism in anionic liposomes revealed secondary-structure differences. Microscale thermophoresis confirmed distinct liposome binding, with mesco-2&#xa0;A likely binding as monomers and mesco-2 forming assemblies, as also suggested by the modelling results. Overall, our findings show that the C-terminal cyclic tail is a tunable element for peptide engineering, enabling control over the speed, extent, and cooperativity of antimicrobial activity.</p>

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Unstructured, disulfide-bridged C-terminus in helminth α-helical antimicrobial peptides enhances and modulates their activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月21日

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  • Anamarija Budimir,
  • Iva Stojan,
  • Korina Primorac,
  • Andrea Caporale,
  • Lucija Krce,
  • Marija Raguž,
  • Sabrina Pacor,
  • Alessandro Tossi,
  • Tomislav Rončević,
  • Larisa Zoranić

摘要

Understanding antimicrobial peptide (AMP) structural determinants is crucial for clinical development. While most designed AMPs are short and helical, many natural ones have unstructured or cyclic C-terminal tails with poorly defined functions. We studied mesco-2 from the flatworm Mesocestoides corti, with an N-terminal α-helix kinked around a palindromic GRGIGRG motif and an unstructured C-terminal tail containing a disulfide-forming CLGRC motif, along with its disulfide-reduced analogue mesco-2 A. Similar CXXXC motifs are common in flatworm AMPs and typically occur in unstructured regions, as indicated by the sequence analysis. Molecular modelling revealed that the C-terminal disulfide loop modulates mesco-2 flexibility and oligomerization. Both peptides displayed strong antibacterial activity and low cytotoxicity. Differences appeared in their effect on bacterial growth kinetics at sub-bactericidal concentrations. Flow cytometry and fluorescence imaging confirmed membrane-related mechanisms, but for mesco-2 A the membrane-disruptive effect was slower. Atomic force microscopy confirmed their distinct membrane interaction modes, and circular dichroism in anionic liposomes revealed secondary-structure differences. Microscale thermophoresis confirmed distinct liposome binding, with mesco-2 A likely binding as monomers and mesco-2 forming assemblies, as also suggested by the modelling results. Overall, our findings show that the C-terminal cyclic tail is a tunable element for peptide engineering, enabling control over the speed, extent, and cooperativity of antimicrobial activity.