Short cationic antimicrobial peptides bind to human alpha-1 acid glycoprotein with no implications for the in vitro bioactivity

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 cat...

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Bibliographic Details
Published in:Journal of molecular recognition 2013-10, Vol.26 (10), p.461-469
Main Authors: Sivertsen, Annfrid, Brandsdal, Bjørn Olav, Svendsen, John Sigurd, Andersen, Jeanette Hammer, Svenson, Johan
Format: Article
Language:English
Subjects:
alpha-1 acid glycoprotein binding
Antiinfectives and antibacterials
Antimicrobial Cationic Peptides - chemistry
Antimicrobial Cationic Peptides - pharmacology
antimicrobial peptides
Bacteria
Binding
Binding Sites
Calorimetry
Cationic
Clinical Trials, Phase II as Topic
Glycoprotein
Humans
In vitro testing
isothermal titration calorimetry
Microbial Sensitivity Tests
molecular docking
Molecular Docking Simulation
Orosomucoid - chemistry
Peptides
Protein Binding
Serum albumin
Staphylococcus aureus - drug effects
Staphylococcus aureus - growth & development
Thermodynamics
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Summary: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. Copyright © 2013 John Wiley & Sons, Ltd. The interactions between human alpha‐1 acid glycoprotein and a series of novel drug‐like cationic antimicrobial peptides have been studied using isothermal calorimetry and docking experiments. It is shown that the binding to alpha‐1 acid glycoprotein does not inflict major implications for the in vitro bactericidal activity of the peptides.
ISSN:0952-3499
1099-1352
DOI:10.1002/jmr.2288