Characterization of the Mechanisms of Broad-Spectrum Viral Entry Inhibitors Open Access
- Other title
Viral fusion inhibitors
Viral attachment inhibitors
- Type of item
- Degree grantor
University of Alberta
- Author or creator
Colpitts, Che C
- Supervisor and department
Schang, Luis (Biochemistry and Medical Microbiology and Immunology)
- Examining committee member and department
Richardson, Christopher (Microbiology and Immunology, Dalhousie University)
Evans, David (Medical Microbiology and Immunology)
Tyrrell, Lorne (Medical Microbiology and Immunology)
West, Frederick (Chemistry)
Department of Medical Microbiology and Immunology
- Date accepted
- Graduation date
Doctor of Philosophy
- Degree level
Viral entry is an attractive antiviral target. Entry inhibitors prevent infection of healthy cells and inhibit viral replication before viruses establish persistent reservoirs. Two entry steps, the primary attachment to cellular glycans and the lipid rearrangements during fusion, are conserved among many unrelated viruses. Therefore, inhibitors of these entry steps, acting through appropriate mechanisms, are likely to have broad-spectrum antiviral activity.
Using small molecules as probes, I identified and characterized three mechanisms by which it is possible to inhibit the entry of unrelated viruses. The majority of human viruses, including enveloped and nonenveloped viruses, initially bind to cellular glycans. Epigallocatechin gallate (EGCG), a green tea polyphenol, competes for virion binding to heparan sulfate or sialic acid moieties in cellular glycans to inhibit the infectivity of most human viruses. All enveloped viruses rely on lipid rearrangements during entry steps. Rigid amphipathic fusion inhibitors (RAFIs) act through biophysical mechanisms to inhibit the formation of the negative membrane curvature required for the fusion of enveloped viruses. Enveloped viruses constitute a large group of human viruses, including most clinically important pathogens. Curcumin and 25-hydroxycholesterol (25HC) modulate the fluidity and composition of lipid membranes to interfere with the replication of hepatitis C virus (HCV) and other enveloped viruses.
None of these small molecules are ideal candidates for antiviral drugs. More importantly, the identification of these mechanisms opens the possibility for the rational design of small molecule entry inhibitors with broad-spectrum antiviral activities and appropriate pharmacological properties. Furthermore, the small molecules described in this thesis are useful as probes to characterize viral entry steps.
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- Citation for previous publication
Colpitts, C.C. and Schang, L.M. (2014) A small molecule inhibits virion attachment to heparan sulfate- or sialic acid-containing glycans. J. Virol. doi: 10.1128/JVI.00896-14Ciesek, S., von Hahn, T., Colpitts, C.C., Schang, L.M., Friesland, M., Steinmann, J., Manns, M.P., Ott, M., Wedermeyer, H., Meuleman, P., Pietschmann, T. and Steinmann, E. (2011) The green tea polyphenol epigallocatechin-3-gallate (EGCG) inhibits hepatitis C virus (HCV) entry. Hepatology 54(6): 1947-55Colpitts, C.C., Ustinov, A.V., Epand, R.F., Epand, R.M., Korshun, V.A. and Schang, L.M. (2013) 5-(Perylen-3-yl)ethynyl-arabino-uridine (aUY11), an arabino-based rigid amphipathic fusion inhibitor, targets virion envelope lipids to inhibit fusion of influenza, hepatitis C and other enveloped viruses. J. Virol. 87(7): 3640-54St.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., Schang, L.M. (2010) Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses. PNAS 107(40): 17339-44Anggakusuma, Colpitts, C.C., Schang, L.M., Rachmawati, H., Frentzen, A., Pfaender, S., Behrendt, P., Brown, R.J., Bankwitz, D., Steinmann, J., Ott, M., Meuleman, P., Rice, C.M., Ploss, A., Pietschmann, T. and Steinmann, E. (2014) Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells. Gut 63(7):1137-49
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