Selective cytotoxicity following Arg-to-Lys substitution in tritrpticin adopting a unique amphipathic turn structure.
In antimicrobial peptides, the cationic property due to basic amino acids has been widely recognized as an important factor to promote electrostatic interaction with negatively charged phospholipids. However, little is known about the differences between two basic residues, Arg and Lys, in membrane binding affinity. Tritrpticin is an Arg- or Trp-rich antimicrobial peptide with a broad spectrum of antibacterial and antifungal activity. To investigate the structural and functional differences between Arg and Lys residues, here we designed and synthesized Arg-containing peptides, tritrpticin and SYM11, and their counterpart Lys-substituted peptides, TRK and SYM11KK, respectively. Although there were no remarkable conformational differences between Arg-containing and Lys-substituted peptides, TRK and SYM11KK exhibited almost two-fold enhanced antibacterial activity but significantly reduced hemolytic activity as compared to tritrpticin and SYM11, respectively. Furthermore, Arg-containing peptides showed strong binding affinity to both zwitterionic and anionic liposomes, whereas Lys-substituted peptides interacted weakly with zwitterionic liposomes but strongly with anionic liposomes. These results suggest that the primary amine of Lys interacts less electrostatically with zwitterionic phospholipids than the guanidinium group of Arg. Our results obtained in this study may be helpful in the design of drugs that target negatively charged phospholipids.
Yang
Sung-Tae
ST
Department of Life Science, Kwangju Institute of Science and Technology, Kwangju 500-712, South Korea.
Shin
Song Yub
SY
Lee
Chul Won
CW
Kim
Yong-Chul
YC
Hahm
Kyung-Soo
KS
Kim
Jae Il
JI
D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry*; D002942:Circular Dichroism; D006461:Hemolysis / Q000187:drug effects*; D008081:Liposomes; D008239:Lysine / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation
D000900:Anti-Bacterial Agents; D008081:Liposomes; D009842:Oligopeptides; C402895:tritrpticin; D001120:Arginine; D008239:Lysine