A bactericidal cecropin-A peptide with a stabilized alpha-helical structure possess an increased killing capacity but no proinflammatory activity.
Antibacterial peptides are part of the innate immune system in a variety of different species including humans. Some of these peptides have also been shown to have effects on immune competent cells such as professional phagocytes. We have recently shown that a cecropin-like peptide from Helicobacter pylori, Hp(2-20), in addition to being bactericidal possesses proinflammatory effects and can recruit and activate neutrophils as well as monocytes. It is well established that cecropins have the ability to adopt amphipathic alpha-helices, which is thought to be required for their bactericidal activity. In this study we show the same structural requirements for Hp(2-20). Breaking the helical structure of Hp(2-20) reduced the antibacterial effect and abolished its proinflammatory activity. A C-terminal truncated cecropin A peptide that highly resembles Hp(2-20) failed to activate neutrophils and computer-based structural simulations revealed a difference between the two peptides in the stability of their helical structures. A hybrid peptide with amino acid substitutions stabilizing the alpha-helical structure of the truncated cecropin A peptide did not introduce any proinflammatory activity; the bactericidal activity was, however, increased. We thus conclude that the proinflammatory effect of Hp(2-20) is a unique sequence-specific feature of the peptide and the ability to adopt a stable amphipathic helix is a necessary but not sufficient criterion for the functional dualism of the peptide.
Fu
Huamei
H
Department of Rheumatology and Inflammation Research, University of Göeborg, Guldhedsgatan 10, S-413 46 Göteborg, Sweden.
Björstad
Ase
A
Dahlgren
Claes
C
Bylund
Johan
J
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D003198:Computer Simulation; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D016480:Helicobacter pylori / Q000737:chemistry; D006801:Humans; D007249:Inflammation; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D019255:NADPH Oxidases / Q000032:analysis / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010455:Peptides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013481:Superoxides / Q000032:analysis
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D010455:Peptides; D013481:Superoxides; C031161:cecropin A; D019255:NADPH Oxidases