Use of Unnatural Amino Acids to Probe Structure–Activity Relationships and Mode-of-Action of Antimicrobial Peptides

  • Alessandro TossiEmail author
  • Marco Scocchi
  • Sotir Zahariev
  • Renato Gennaro
Part of the Methods in Molecular Biology book series (MIMB, volume 794)


Endogenous antimicrobial peptides (AMPs) can have multimodal mechanisms of bacterial inactivation, such as membrane lysis, interference with cell wall biosynthesis or membrane-based protein machineries, or translocation through the membrane to intracellular targets. The controlled variation of side-chain characteristics in their amino acid residues can provide much useful information on structure–activity relationships and mode-of-action, and also lead to improved activities. The small size and relatively low complexity of AMPs make them amenable to solid-phase peptide synthesis, facilitating the use of nonproteinogenic amino acids and vastly increasing the accessible molecular diversity of side chains. Here, we describe how such residues can be used to modulate such key parameters as cationicity, hydrophobicity, steric factors conformational stability, and H-bonding.

Key words

Unnatural amino acids Nonproteinogenic amino acids Antimicrobial peptide Host defence peptide SAR studies Solid-phase peptide synthesis 



Amino acid






Diisopropyl carbodiimide






















Succinimidyl carbonate




Side-chain protecting group




(Benzotriazol-1-yl-oxy)tripyrrolidinophosphonium hexafluoro phosphate


Swelled resin volume


Solid-phase peptide synthesis





This work was supported by the Friuli Venezia Giulia LR 26 regional grant R3A2.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Alessandro Tossi
    • 1
    Email author
  • Marco Scocchi
    • 1
  • Sotir Zahariev
    • 2
  • Renato Gennaro
    • 1
  1. 1.Department of Life SciencesUniversity of TriesteTriesteItaly
  2. 2.International Centre for Genetic Engineering and BiotechnologyTriesteItaly

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