Novel Stapling by Lysine Tethering Provides Stable and Low Hemolytic Cationic Antimicrobial Peptides

J Med Chem. 2020 Apr 23;63(8):4081-4089. doi: 10.1021/acs.jmedchem.9b02025. Epub 2020 Apr 8.


Cationic antimicrobial peptides (CAMPs) are potent therapeutics for drug-resistant bacterial infections. However, the clinical application of CAMPs is hampered by its poor proteolytic stability and hemolytic activity toward eukaryotic cells. Great efforts have been made to design and generate derivatives of CAMPs with improved pharmacological properties. Here, we report a novel stapling protocol, which tethers two ε-amino groups of the lysine residue by the N-alkylation reaction on the hydrophilic face of amphiphilic antimicrobial peptides. A series of lysine-tethered stapled CAMPs were synthesized, employing the antimicrobial peptide OH-CM6 as a model. Biological screening of the stapled CAMPs provided an analogue with strong antimicrobial activity, high proteolytic stability, and low hemolytic activity. This novel stapling approach offers an important chemical tool for developing CAMP-based antibiotics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antimicrobial Cationic Peptides / chemistry*
  • Antimicrobial Cationic Peptides / metabolism
  • Antimicrobial Cationic Peptides / pharmacology*
  • Escherichia coli / drug effects
  • Escherichia coli / physiology
  • HEK293 Cells
  • Hemolysis / drug effects*
  • Hemolysis / physiology
  • Humans
  • Lysine / chemistry*
  • Lysine / metabolism
  • Lysine / pharmacology*
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Methicillin-Resistant Staphylococcus aureus / physiology
  • Microbial Sensitivity Tests / methods


  • Antimicrobial Cationic Peptides
  • Lysine