Structure dependence of biological activities for primate cathelicidins.
We have analysed the effects of variations in orang-utan (ppy), rhesus macaque (mmu) and leaf eater (pob) monkey orthologues of the human cathelicidin LL-37, on a range of relevant biological activities. These host defence peptides range in cationicity from +4 to +10, and while the more cationic pob and mmuRL-37 are in a monomeric and unstructured form in bulk solution (F-form), the human and ppyLL-37 are in an aggregated/helical form (A-form). The in vitro antibacterial activity depended strongly on both the structural form and the charge. F-form peptides were more potent against Gram-positive and -negative bacteria and less salt, medium or serum sensitive than A-form ones. CD studies suggested that A- and F-form peptides interact with LPS in different manners, but the ability to detoxify it did not correlate directly with either the charge or structure. Toxicity towards eukaryotic cells also showed a varied dependence on the peptides' physical characteristics. Haemolytic activity was similar for all the tested peptides while other cytotoxicity assays revealed the highly cationic, F-form pobRL-37 as the most toxic, followed by the A-form human LL-37. As shown with the human peptide, toxicity depended markedly on the nature and metabolic state of the target cell. Our results suggest that different evolutionary trajectories for each orthologue lead to distinct sets of physical characteristics, which significantly differentiates their biological activities.
Tomasinsig
Linda
L
Department of Biomedical Sciences and Technology, University of Udine, Udine, Italy.
Morgera
Francesca
F
Antcheva
Nikolinka
N
Pacor
Sabrina
S
Skerlavaj
Barbara
B
Zanetti
Margherita
M
Tossi
Alessandro
A
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D054804:Cathelicidins / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000882:Haplorhini; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008253:Macaca mulatta; D051379:Mice; D008826:Microbial Sensitivity Tests; D041681:NIH 3T3 Cells; D011148:Pongo pygmaeus; D011323:Primates
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D008070:Lipopolysaccharides