Back to Search
Start Over
The NEU1-selective sialidase inhibitor, C9-butyl-amide-DANA, blocks sialidase activity and NEU1-mediated bioactivities in human lung in vitro and murine lung in vivo.
The NEU1-selective sialidase inhibitor, C9-butyl-amide-DANA, blocks sialidase activity and NEU1-mediated bioactivities in human lung in vitro and murine lung in vivo.
- Source :
-
Glycobiology [Glycobiology] 2016 Aug; Vol. 26 (8), pp. 834-49. Date of Electronic Publication: 2016 May 25. - Publication Year :
- 2016
-
Abstract
- Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total sialidase activity whereas PPCA expression did not. In contrast to eukaryotic sialidases, C9-BA-DANA exerted far less inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the β-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo.<br /> (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Animals
Bacterial Proteins genetics
Bacterial Proteins metabolism
Cathepsin A genetics
Cathepsin A metabolism
Cell Movement drug effects
Endothelial Cells cytology
Endothelial Cells drug effects
Endothelial Cells enzymology
Endothelium, Vascular cytology
Endothelium, Vascular drug effects
Endothelium, Vascular enzymology
Epithelial Cells cytology
Epithelial Cells drug effects
Epithelial Cells enzymology
Fibroblasts cytology
Fibroblasts drug effects
Fibroblasts enzymology
Flagellin antagonists & inhibitors
Flagellin pharmacology
Gene Expression Regulation
Humans
Hydrolysis
Isoenzymes antagonists & inhibitors
Isoenzymes genetics
Isoenzymes metabolism
Lung cytology
Lung enzymology
Mice
Models, Molecular
Mucin-1 genetics
Mucin-1 metabolism
N-Acetylneuraminic Acid analogs & derivatives
N-Acetylneuraminic Acid chemistry
Neuraminidase genetics
Neuraminidase metabolism
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Domains
Protein Interaction Domains and Motifs
Pseudomonas aeruginosa chemistry
Enzyme Inhibitors pharmacology
Lung drug effects
Mucin-1 chemistry
N-Acetylneuraminic Acid pharmacology
Neuraminidase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2423
- Volume :
- 26
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Glycobiology
- Publication Type :
- Academic Journal
- Accession number :
- 27226251
- Full Text :
- https://doi.org/10.1093/glycob/cww060