title: Short cationic antimicrobial peptides bind to human alpha-1 acid glycoprotein with no implications for the in vitro bioactivity.
abstract: Several drugs interact with the major plasma proteins serum albumin and alpha-1 acid glycoprotein. Such binding may be either beneficial or disadvantageous from a pharmacokinetic perspective. In the present paper, we investigate the thermodynamics involved in the binding of a series of promising cationic antimicrobial peptides to the alpha-1 acid glycoprotein using isothermal titration calorimetry. The drug-like peptides are able to effectively destroy multiresistant bacterial strains, and members of this peptide class are currently in clinical phase II trials. Similar peptides, in a previous study, have been shown to bind to serum albumin resulting in a 10-fold reduction in the peptides ability to kill bacteria in vitro. Here, it is shown that the peptides also are ligands for alpha-1 glycoprotein with moderate binding affinities. The binding mode is investigated in detail using molecular docking, which maps the interaction to sub-pockets I, II and III of the binding site. Despite this interaction, protein binding is shown to have little or no effect on the ability of the peptides to kill bacteria in vitro, either at normal physiological or acute phase concentrations. The results show that although the peptides interact with the binding pocket of alpha-1 acid glycoprotein, the low stoichiometric binding ratio ensures that the interaction is not an obstacle for further development of these promising peptides as antimicrobial therapies.
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, Faculty of Science and Technology, University of Tromsø, NO-9037, Tromsø, Norway.
authors.forename: Annfrid
authors.initials: A
authors.lastname: Sivertsen
authors.forename: Bjørn Olav
authors.initials: BO
authors.lastname: Brandsdal
authors.forename: John Sigurd
authors.initials: JS
authors.lastname: Svendsen
authors.forename: Jeanette Hammer
authors.initials: JH
authors.lastname: Andersen
authors.forename: Johan
authors.initials: J
authors.lastname: Svenson
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002151:Calorimetry; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009961:Orosomucoid / Q000737:chemistry*; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013816:Thermodynamics
chemical_list: D023181:Antimicrobial Cationic Peptides; D009961:Orosomucoid
keywords: alpha-1 acid glycoprotein binding; antimicrobial peptides; isothermal titration calorimetry; molecular docking