Novel Stapling by Lysine-tethering Provides Stable and Low Hemolytic Cationic Antimicrobial Peptide.

Cationic antimicrobial peptides (CAMPs) are potent therapeutics for drug-resistant bacterial infections. However, the clinical applica-tion 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 lysine residue by N-alkylation reaction on the hydrophilic face of amphiphilic antimicrobial peptide. A series of lysine-tethered stapled CAMPs was synthesized employing the antimicrobial peptide OH-CM6 as model. Biological screening of the stapled CAMPs provided an ana-logue with strong antimicrobial activity, high proteolytic stability and low hemolytic activity. This novel stapling approach offers an important chemical tool for developing CAMPs based antibiotics.