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

  • Author / Creator
    Albohy, Amgad M R
  • 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.

  • Subjects / Keywords
  • Graduation date
    2014-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3Q33J
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • Cairo, Christopher W. (Chemistry)
  • Examining committee members and their departments
    • Gibbs-Davis, Julianne M. (Chemistry)
    • Bundle, David R. (Chemistry)
    • Klassen, John (Chemistry)
    • Cloninger, Mary (Chemistry and Biochemistry, Montana State University)
    • Sipione, Simonetta (Pharmacology)