New strategies for influenza detection and anti-influenzas studies
Date Issued
2011
Date
2011
Author(s)
Su, Ching-Yao
Abstract
The appearance of the highly pathogenic H5N1 avian flu and the pandemic H1N1 swine flu cause serious alarms because the existing influenza vaccine is insufficient to prevent the spread of these viruses. The neuraminidase inhibitors are the most effective therapeutic measures we have at this time. Unfortunately, the seasonal flu since 2009 were almost all resistant to oseltamivir. The oseltamivir resistant mutant was also found in patients infected with the highly pathogenic H5N1 avian flu and H1N1 swine flu. The general concern is that whether future pandemic influenza virus will be oseltamivir resistant or not. Therefore, other prophylactics and therapeutic compounds are necessary for preventing influenza infection. The bioassays to study anti-influenza leads, the compound modifications for more efficacious neuraminidase inhibitors, the screenings to identify new anti-influenza inhibitors, the diagnostic tools for oseltamivir resistant viruses and new vaccine development for pandemic influenza are important. Toward these objectives, we developed new cell-base neuraminidase inhibition assay by measuring the releases of HA pseudotype particle (HApp). HApp release assay allows to measure the potencies of the neuraminidase inhibitors under physiological conditions. We studied the mechanism of a potent neuraminidase inhibitor, zanamivir porphyrin, that contains four zanamivirs linked to porphyrin. Zanamivir porphyrin is more efficacious than zanamivir in influenza infectivity and HApp release assays. We also elucidated the mode of action of a new anti-influenza compound identified by HTS. The anti-influenza, compound 3061, targeted influenza NP and affected the activity of RdRP (RNA dependent RNA polymerase). A novel RABC assay (Resistant Assessment by Binding Competition) was developed to determine the oseltamivir susceptibility of influenza neuraminidase. It is also combined with glycan array (influenza HA-binding specificity) to allow a quick and simple test for oseltamivir susceptibility and influenza HA typing. Finally, we also prepared mg HA-VLP (monoglycosylated hemagglutinin virus like particle) that is more effective than fg HA-VLP in preventing influenza infection.
Subjects
virus detection
anti-influenza drug
pseudotype virus
SDGs
Type
thesis
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