In silico identification and biological evaluation of antimicrobial peptides based on human cathelicidin LL-37.
Bacterial lipopolysaccharides (LPS) are important triggers of the widespread inflammatory response, which contributes to the development of multiple organ failure during sepsis. The helical 37-amino-acid-long human antimicrobial peptide LL-37 not only possesses a broad-spectrum antimicrobial activity but also binds and neutralizes LPS. However, the use of LL-37 in sepsis treatment is hampered by the fact that it is also cytotoxic. To find a less toxic analog of LL-37, we used in silico analysis to identify amphipathic helical regions of LL-37. A 21-amino-acid fragment (GKE) was synthesized, the biological actions of which were compared to those of two equally long peptides derived from the N and C termini of LL-37 as well as native LL-37. GKE displayed antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Candida parapsilosis that was similar to or even stronger than LL-37. GKE, as well as the equally long control peptides, attracted granulocytes in a fashion similar to that of LL-37, while only GKE was as potent as LL-37 in inhibiting LPS-induced vascular nitric oxide production. GKE caused less hemolysis and apoptosis in human cultured smooth muscle cells than LL-37. In summary, we have identified an active domain of LL-37, GKE, which displays antimicrobial activity in vitro and LPS-binding activity similar to those of LL-37 but is less toxic. GKE therefore holds promise as a template for the development of peptide antibiotics for the treatment of sepsis.
Sigurdardottir
Thorgerdur
T
Department of Anesthesiology and Intensive Care, Lund University, Lund, Sweden.
Andersson
Pia
P
Davoudi
Mina
M
Malmsten
Martin
M
Schmidtchen
Artur
A
Bodelsson
Mikael
M
D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D008081:Liposomes; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D018805:Sepsis / Q000188:drug therapy; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008070:Lipopolysaccharides; D008081:Liposomes; D009566:Nitrates; D009573:Nitrites; D010446:Peptide Fragments; D054804:Cathelicidins