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Permanent link (DOI): https://doi.org/10.7939/R3Q33J

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Structure-based design of inhibitors for the human neuraminidase enzymes NEU2, NEU3, and NEU4 Open Access

Descriptions

Other title
Subject/Keyword
Human sialidases
Enzyme inhibitors
Neuraminidases
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Albohy, Amgad M R
Supervisor and department
Cairo, Christopher W. (Chemistry)
Examining committee member and department
Cloninger, Mary (Chemistry and Biochemistry, Montana State University)
Klassen, John (Chemistry)
Gibbs-Davis, Julianne M. (Chemistry)
Sipione, Simonetta (Pharmacology)
Bundle, David R. (Chemistry)
Department
Department of Chemistry
Specialization

Date accepted
2014-03-28T09:36:47Z
Graduation date
2014-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Sialidases (neuraminidases) are a group of enzymes responsible for the hydrolysis of sialic acid from glycoconjugates. In humans, there are four different isoenzymes that play important roles in health and disease. The human neuraminidase enzymes (hNEU) were discovered somewhat recently, and there are few known inhibitors. In this thesis we present studies towards the development of inhibitors for the human sialidases, NEU2, NEU3 and NEU4. We used the reported crystal structure of NEU2, and homology models of NEU3 and NEU4, to understand the substrate recognition by these enzymes. Our models were tested using site directed mutagenesis. Molecular modeling was used to design selective, potent inhibitors. Most notably, we report the design and testing of a highly selective nanomolar inhibitor of NEU4. In addition, an STD NMR study of NEU3 with an analog of GM3 provides insight into substrate recognition by this important enzyme. These results provide a critical foundation for future development of inhibitors and tools for understanding the role of these enzymes in human health.
Language
English
DOI
doi:10.7939/R3Q33J
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Albohy, A.; Li, M. D.; Zheng, R. B.; Zou, C.; Cairo, C. W., Insight into substrate recognition and catalysis by the human neuraminidase 3 (NEU3) through molecular modeling and site-directed mutagenesis. Glycobiology 2010, 20 (9), 1127-1138Albohy, A.; Zhang, Y.; Smutova, V.; Pshezhetsky, A. V.; Cairo, C. W., Identification of Selective Nanomolar Inhibitors of the Human Neuraminidase, NEU4. ACS Med Chem Lett 2013, 4 (6), 532-537Zou, Y.; Albohy, A.; Sandbhor, M.; Cairo, C. W., Inhibition of human neuraminidase 3 (NEU3) by C9-triazole derivatives of 2,3-didehydro-N-acetyl-neuraminic acid. Bioorganic & Medicinal Chemistry Letters 2010, 20 (24), 7529-7533Zhang, Y.; Albohy, A.; Zou, Y.; Smutova, V.; Pshezhetsky, A. V.; Cairo, C. W., Identification of Selective Inhibitors for Human Neuraminidase Isoenzymes Using C4,C7-Modified 2-Deoxy-2,3-didehydro-N-acetylneuraminic Acid (DANA) Analogues. J Med Chem 2013, 56 (7), 2948-2958.Albohy, A.; Mohan, S.; Zheng, R. X. B.; Pinto, B. M.; Cairo, C. W., Inhibitor selectivity of a new class of oseltamivir analogs against viral neuraminidase over human neuraminidase enzymes. Bioorganic & Medicinal Chemistry 2011, 19 (9), 2817-2822.

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