THESIS
2018
xv, 86 pages : illustrations (some color) ; 30 cm
Abstract
Influenza A virus has caused a wide spreading pandemic in the past century. The four
serious pandemics including "the 1968 Hong Kong flu", has caused millions of deaths
around the world. In this case, antiviral inhibitor discovery has gradually been
considered as a promising way of treating influenza A virus epidemics. The most
commonly used antiviral inhibitors in public are M2 proton channel inhibitors and
neuraminidase inhibitors. But both target proteins protrude on the surface of viral
capsid, their conformational changes can lead to the unbinding of inhibitors, and
further to the resistance to these inhibitors. Therefore, we have discovered some
potential molecular inhibitors to the treatment of influenza A virus. To have a
high-throughput screening efficiency and bette...[
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Influenza A virus has caused a wide spreading pandemic in the past century. The four
serious pandemics including "the 1968 Hong Kong flu", has caused millions of deaths
around the world. In this case, antiviral inhibitor discovery has gradually been
considered as a promising way of treating influenza A virus epidemics. The most
commonly used antiviral inhibitors in public are M2 proton channel inhibitors and
neuraminidase inhibitors. But both target proteins protrude on the surface of viral
capsid, their conformational changes can lead to the unbinding of inhibitors, and
further to the resistance to these inhibitors. Therefore, we have discovered some
potential molecular inhibitors to the treatment of influenza A virus. To have a
high-throughput screening efficiency and better inhibitor potency such as
permeability and solubility, small molecules with potential antiviral effect due to the
literature were chosen. To reduce the structural changes effect by genetic variation,
we choose a more functional enzyme of influenza A virus with more conserved
sequence as the target receptor: influenza A virus polymerase. To test and select
potential candidate inhibitors from small molecular compounds library, viral
polymerase was expressed in vitro and the inhibitor screening experiment was done.
In addition, we used computational simulation method to explore the binding modes
between identified inhibitors and influenza A virus polymerase. In particular, the
molecular docking method was applied, which could rank multiple binding modes by factors as binding affinity and number of hydrogen bonds. There are some positive
potential candidates selected from inhibitor screening experiment, which have limited
cytotoxicity value and sufficient inhibitive value from the testing of LDH
cytotoxicity assay and luciferase assay, respectively. These identified small molecular
compounds hold potential to be further developed as inhibitors against influenza A virus. In
the future, we plan to further elucidate the molecular mechanisms of these inhibitors
binding to virus polymerase via the combination of experimental and simulation
approaches.
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