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Title: Iminosugars as antivirals against human influenza A viruses
Author: Hussain, S.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Influenza A viruses cause seasonal epidemics and pandemics in the human population, resulting in significant morbidity and mortality. Influenza can be controlled by vaccination and antiviral therapy. However, antigenic drift, reducing vaccine effectiveness, and the development of antiviral resistance can result in reduced efficacy of the control measures. Drugs that target host cell processes, such as glycosylation, may be employed to complement drugs that target the virus, and iminosugar compounds which inhibit α-glucosidases have been reported to show antiviral activity against some viruses. Here, I have examined the effect of two iminosugars on human influenza A viruses. I have shown that two α-glucosidase inhibitors, N-butyl deoxynojirimycin (NB-DNJ) and N-nonyl deoxynojirimycin (NN-DNJ), show antiviral activity in cell culture against three human influenza A viruses: a recently circulating seasonal H3N2 virus strain, A/Brisbane/10/2007, an older H3N2 strain, A/Udorn/307/72, and a representative of the currently circulating pandemic H1N1 virus, A/Lviv/N6/2009. Of the two, NN-DNJ was the more potent drug. The virus target and mode of action of NN-DNJ has been examined. The effect of the drug was most marked after infection. Consistent with its action as an α-glucosidase inhibitor, NN-DNJ treatment resulted in altered glycan processing, as shown by a reduction in electrophoretic mobility of both influenza virus glycoproteins, haemagglutinin (HA) and neuraminidase (NA). NN-DNJ treatment was found to reduce cell surface expression of H3 HA. The level of sialidase activity of NA was reduced in the infected cell, however addition of exogenous sialidase to cells did not complement NN-DNJ mediated inhibition of virus replication. Using reassortant viruses, the drug susceptibility profile correlated with the HA. Reverse genetics was used to determine the effect of altering the glycosylation status of the HA; engineered viruses carrying modified sites seemed slightly more sensitive to the inhibitor than the parent virus. These results show that NN-DNJ inhibits influenza A virus replication in a strain-specific manner which is dependent on the HA.
Supervisor: McCauley, J. ; Rosenthal, P. B. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available