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The Discovery and Characterization of Rigid Amphipathic Fusion Inhibitors (RAFIS), a Novel Class of Broad-Spectrum Antiviral Compounds Open Access
- Other title
small molecule compounds
Hepatitis C virus
lipid bilayer curvature
Rigid Amphipathic Fusion Inbitors (RAFIs)
- Type of item
- Degree grantor
University of Alberta
- Author or creator
St.Vincent, Mireille RM
- Supervisor and department
Schang, Luis (Biochemistry)
- Examining committee member and department
Schang, Luis (Biochemistry)
Jean, Francois (Microbiology and Immunology)
Holmes, Charles (Biochemistry)
Tyrrell, Lorne (Medical Microbiology and Immunology)
Evans, David (Medical Microbiology and Immunology)
Department of Biochemistry
- Date accepted
- Graduation date
Doctor of Philosophy
- Degree level
Antiviral drugs targeting viral proteins or their interactions with cellular proteins lead to rapid selection for resistance. Moreover, the number of viral targets is limited. Novel antiviral targets are needed. The unique characteristics of fusion between virion envelopes and cell membranes may provide such targets. Like all fusing bilayers, virion envelopes must locally convert to negative curvature to form hourglass-shaped hemifusion stalks. Unlike cellular vesicles, virion envelopes fuse to the outer leaflets of cell membranes without lipid redistribution between leaflets, and using only the energy released by glycoprotein binding and rearrangement. Enrichment in inverted-cone shaped lysophospholipids in the outer leaflet of vesicles disfavors negative curvature, inhibiting fusion. Such lipids, however, are toxic and not pharmacologically useful.
My hypothesis is that pharmacologically useful small amphipathic molecules of appropriate shape (hydrophilic region of larger crosssection than the hydrophobic one) can intercalate within virion lipids, inhibiting the formation of the negative curvature required for fusion of all enveloped viruses.
Herein, I report the discovery and characterization of the novel antiviral mechanisms of a novel family of rigid amphipathic nucleosides. One such compound, dUY11, disfavors the formation of the required negative curvature. Exposure to dUY11 inhibits the infectivity of several otherwise unrelated enveloped viruses (IC50, 50 nM), including hepatitis C and genital herpes virus. dUY11 has no major cytotoxic/static effects (SI>1,800). dUY11 does not inhibit viral DNA replication, but inhibits infectivity produced by cells treated after infection, even with acyclovir or phosphonoacetic acid resistant strains. The targets of dUY11 are not encoded in the viral genomes. Consistently, resistance to dUY11 has not been detected.
This thesis serves as proof-of-concept that small molecule fusion inhibitors targeting envelope bilayer curvature are viable antiviral strategies. These strategies may help in overcoming the limitations of clinical antivirals, including narrow specificity and rapid resistance selection. dUY11 inhibits infection and acts extracellularly, highly desirable properties for microbicides. dUY11 has therapeutic potential, too, targeting and inhibiting functions conserved among all otherwise unrelated enveloped viruses. The novel antiviral mechanisms of action presented herein may impact future development of prophylactic and therapeutic antivirals.
- 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
St Vincent, M. R., Colpitts, C. C., Ustinov, A. V., Muqadas, M., Joyce, M. A., Barsby, N. L., Epand, R. F., Epand, R. M., Khramyshev, S. A., Valueva, O. A., Korshun, V. A., Tyrrell, D. L. J., and Schang, L. M. (2010). Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses. Proceedings of the National Academy of Sciences of the United States of America 107(40), 17339-17344.
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File title: titlewithdesignationF.pdf
File title: titlewithdesignationF
File author: Mireille St. Vincent
Page count: 407