Antimicrobial and anti-inflammatory activities of designed antimicrobial peptide P18 analogues.
To develop antimicrobial peptides having higher bacterial selectivity than a novel antimicrobial peptide P18, we synthesized several analogues. The P18 analogues are designed by movement of the N-terminal Trp2 residue in P18 (P18-W6, P18-W8 and P18-W15) and the substitution of the central Pro9 residue with D-Pro or Nala (P18-Nala9 and P18-D-Pro9). These analogues retained potent antibacterial activity but displayed less hemolytic activity than P18. From the viewpoint of their therapeutic index, P18 analogues had approximate 3- to 7-fold higher bacterial selectivity compared to P18. The analogues preferentially bind to bacterial membrane-mimicking negatively charged liposomes as well as does P18. Their high specificity to negatively charged phospholipids corresponds well with their high bacterial selectivity. Furthermore, P18-W6, P18-W8 and P18-Nala9 induced a significant inhibition in NO production from LPS-stimulated macrophage RAW264.7 cells, as well as P18. This result suggests that these peptides appear to have promising therapeutic potential for future development as a novel anti-inflammatory agent as well as antimicrobial agent.
Department of Cellular & Molecular Medicine, School of Medicine, Department of Bio-Materials, Graduate School and Research Center for Proteineous Materials, Chosun University, Gwangju 501-759, Korea.
Yong Hai
YH
Nan
Song Yub
SY
Shin
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002417:Cattle; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D009573:Nitrites / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013379:Substrate Specificity; D014364:Tryptophan / Q000378:metabolism
D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D023181:Antimicrobial Cationic Peptides; D009573:Nitrites; C447608:P18 antimicrobial peptide; D010743:Phospholipids; D014364:Tryptophan