title: Identification of Selective Nanomolar Inhibitors of the Human Neuraminidase, NEU4.
abstract: The human neuraminidase enzymes (hNEU) play important roles in human physiology and pathology. The lack of potent and selective inhibitors toward these enzymes has limited our understanding of their function and the development of therapeutic applications. Here we report the evaluation of a panel of compounds against the four human neuraminidase isoenzymes. Among the compounds tested, we identified the first selective, nanomolar inhibitors of the human neuraminidase 4 enzyme (NEU4). The most potent NEU4 inhibitor (5-acetamido-9-[4-hydroxymethyl[1,2,3]triazol-1-yl]-2,3,5,9-tetradeoxy-d-glycero-d-galacto-2-nonulopyranosonic acid) was found to have an inhibitory constant (K i ) of 30 ± 19 nM and was 500-fold selective for its target over the other hNEU isoenzymes tested in vitro (NEU1, NEU2, and NEU3). This is the first report of any inhibitor of hNEU with nanomolar potency, and this confirms that the 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA) scaffold can be exploited to develop new, potent, and selective inhibitors that target this important family of human enzymes.
authors.affiliation: Alberta Glycomics Center, Department of Chemistry, University of Alberta , Edmonton Alberta T6G 2G2, Canada.
authors.forename: Amgad
authors.initials: A
authors.lastname: Albohy
authors.affiliation: Alberta Glycomics Center, Department of Chemistry, University of Alberta , Edmonton Alberta T6G 2G2, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Medical Genetics, Centre Hospitaliere Universitaire Sainte-Justine, University of Montreal , Montreal, Quebec, Canada, and Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University , Montreal, Quebec, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Smutova
authors.affiliation: Division of Medical Genetics, Centre Hospitaliere Universitaire Sainte-Justine, University of Montreal , Montreal, Quebec, Canada, and Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University , Montreal, Quebec, Canada.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
authors.affiliation: Alberta Glycomics Center, Department of Chemistry, University of Alberta , Edmonton Alberta T6G 2G2, Canada.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cairo
keywords: NEU1; NEU2; NEU3; NEU4; Neuraminidase; glycosyl hydrolase; inhibitors; sialic acid; sialidase