Inhibitors for the bacterial ectonucleotidase Lp1NTPDase from Legionella pneumophila
| Autor: | Christa E. Müller, Wenjin Li, Sang Yong Lee, Patrice Newton, Enas M. Malik, Younis Baqi, Amelie Fiene, Elizabeth L. Hartland |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry Pharmaceutical Science Virulence Biochemistry Legionella pneumophila Catalysis Microbiology 03 medical and health sciences chemistry.chemical_compound ATP hydrolysis Drug Discovery medicine Enzyme Inhibitors Molecular Biology Adenosine Triphosphatases chemistry.chemical_classification biology Hydrolysis Spectrum Analysis Organic Chemistry Electrophoresis Capillary biology.organism_classification medicine.disease Enzyme assay Kinetics 030104 developmental biology Enzyme chemistry biology.protein Nucleoside triphosphate Molecular Medicine Legionnaires' disease Bacteria |
| Zdroj: | Bioorganic & Medicinal Chemistry. 24:4363-4371 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2016.07.027 |
| Popis: | Legionella pneumophila is an aerobic, Gram-negative bacterium of the genus Legionella, which constitutes the major causative agent of Legionnaires' disease. Recently a nucleoside triphosphate diphosphohydrolase (NTPDase) from L. pneumophila was identified and termed Lp1NTPDase; it was found to be a structural and functional homolog of mammalian NTPDases catalyzing the hydrolysis of ATP to ADP and ADP to AMP. Its activity is believed to contribute to the virulence of Legionella pneumophila. Therefore Lp1NTPDase inhibitors are considered as novel antibacterial drugs. However, only weakly potent compounds are available so far. In the present study, a capillary electrophoresis (CE)-based enzyme assay for monitoring the Lp1NTPDase activity was established. The enzymatic reaction was performed in a test tube followed by separation of substrate and products by CE and subsequent quantification by UV analysis. After kinetic characterization of the enzyme, a series of 1-amino-4-ar(alk)ylamino-2-sulfoanthraquinone derivatives structurally related to the anthraquinone dye Reactive Blue 2, a non-selective ecto-NTPDase inhibitor, was investigated for inhibitory activity on Lp1NTPDase using the CE-based enzyme assay. Derivatives bearing a large lipophilic substituent (e.g., fused aromatic rings) in the 4-position of the 1-amino-2-sulfoanthraquinone showed the highest inhibitory activity. Compounds with IC50 values in the low micromolar range were identified. The most potent inhibitor was 1-amino-4-[phenanthrene-9-yl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (28, PSB-16131), with an IC50-value of 4.24μM. It represents the most potent Lp1NTPDase inhibitor described to date. These findings may serve as a starting point for further optimization. Lp1NTPDase inhibition provides a novel approach for the (immuno)therapy of Legionella infections. |
| Databáze: | OpenAIRE |
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