Influenza drug resistance // Drug Repurposing

Influenza drug resistance

Abstract Image† Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675, Japan

‡Influenza Virus Research Center and Department of Pathology, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan

§ Department of General Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

Department of Life and Environmental Science, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino-shi, Chiba 275-0016, Japan

ACS Chem. Biol., 2012, 7 (3), pp 552–562

DOI: 10.1021/cb200332k

# Author Contributions

These authors contributed equally to this work.

Section:

Abstract

Highly pathogenic influenza viruses have become a global threat to humans. It is important to select an effective therapeutic option suitable for the subtypes in an epidemic or pandemic. To increase the options, the development of novel antiviral agents acting on targets different from those of the currently approved drugs is required. In this study, we performed molecular dynamics simulations on a spike protein on the viral envelop, hemagglutinin, for the wild-type and three kinds of mutants using a model system consisting of a trimeric hemagglutinin complex, viral lipid membrane, solvation waters, and ions. A natural product, stachyflin, which shows a high level of antiviral activity specific to some subtypes of influenza viruses, was examined on binding to the wild-type hemagglutinin by docking simulation. The compound potency of stachyflin is, however, easily lost due to resistant mutations. From a comparison of simulation results between the wild-type and the resistant mutants, the reason for the drug resistance of hemagglutinin was clarified. Next, 8 compounds were selected from a chemical database by in silico screening, considering the findings from the simulations. Inhibitory activities to suppress the proliferation of influenza virus were measured by cell-based antiviral assays, and two chemical scaffolds were found to be potent for an inhibitor. More than 30 derivatives bearing either of these two chemical scaffolds were synthesized, and cell culture assays were carried out to evaluate the compound potency. Several derivatives displayed a high compound potency, and 50% effective concentrations of two synthesized compounds were below 1 μM.

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Actually, more chance resistant form.

by rent_this_id

Hydros reply below is worded more correctly imo:
>>7. What researchers suggest that vaccination is dangerous because of the genetic pressures? And even if there were genetic pressures, the WORST that would happen is we end up with an influenzavirus that we can't vaccinate against. It won't magically become extra-deadly because we vaccinated against its long-lost ancestor strains.<<
Selection pressure doesn't result in a more virulent form, however, there is ample evidence that a virus can become very quickly resistant to vaccines. Thus, more chance of a resistant form persisting and spreading

I think you're a little off

by Hydrogyrophage

Tamiflu is a drug, not a vaccine. Resistance to drugs happens quickly with drug pressure.
But "resistance" to vaccines only happens when the antigens of the virus particle mutate to be unrecognizable by antibodies. Vaccines do not increase evolutionary pressure for viruses to mutate more quickly - influenza and other RNA viruses already mutate at the maximally efficient level. If they were to mutate any quicker, they wouldn't be able to cause a successful infection, because they would produce too many non-functional virus particles during replication. This has been studied and confirmed in laboratories using several RNA viruses as models, including influenza

Patrick your slipping

by StinkPalm

You haven't posted this one yet and here I thought you were keeping up on swine flu : P
Swine flu 'shows drug resistance'
Experts have reported the first case of swine flu that is resistant to tamiflu - the main drug being used to fight the pandemic.
Roche Holding AG confirmed a patient with H1N1 influenza in Denmark showed resistance to the antiviral drug.
David Reddy, company executive, said it was not unexpected given that common seasonal flu could do the same.
The news comes as a nine-year-old girl has become the third to die in the UK with swine flu

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