Cell selectivity and mechanism of action of short antimicrobial peptides designed from the cell-penetrating peptide Pep-1

✍ Scribed by Wan Long Zhu; Kyung-Soo Hahm; Song Yub Shin

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 208 KB
• Volume: 15
• Category: Article
• ISSN: 1075-2617
• DOI: 10.1002/psc.1145

✦ Synopsis

Abstract

Pep‐1‐K (PK) is a good cell‐selective antimicrobial peptide designed from cell‐penetrating peptide Pep‐1. To develop novel short antimicrobial peptides with higher cell selectivity and shorter length compared with PK, several PK analogs were designed by the deletion, addition and/or substitution of amino acids. Among these analogs, PK‐12‐KKP (KKPWWKPWWPKWKK) showing the sequence and structure homology with a Trp/Pro‐rich natural antimicrobial peptide, indolicidin (IN), displayed a 20‐fold higher cell selectivity as compared to IN. Circular dichroism analysis revealed that PK‐12‐KKP adopts a folded structure combined with some portions of unordered structure. PK‐12‐KKP selectively binds to negatively charged bacterial membrane–mimetic vesicles, and its high phospholipid selectivity corresponds well with its high cell selectivity. Moreover, it showed very weak potential in depolarization of the cytoplasmic membrane of Staphylococcus aureus at 8 µM (4× minimal inhibitory concentration) and dye leakage from negatively charged liposomes. These results suggest that the ultimate target of our designed PK‐12‐KKP maybe the intracellular components (e.g. protein, DNA or RNA) rather than the cytoplasmic membranes. Collectively, our designed short Trp/Pro‐rich peptide, PK‐12‐KKP, appears to be an excellent candidate for future development as a novel antimicrobial agent. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.