Abstract
Seasonal influenza epidemics lead to 3-5 million severe infections and 290,000-650,000 annual global deaths. With deaths from the 1918 influenza pandemic estimated at >50,000,000 and future pandemics anticipated, the need for a potent influenza treatment is critical. In this study, we design and synthesize a bifunctional small molecule by conjugating the neuraminidase inhibitor, zanamivir, with the highly immunogenic hapten, dinitrophenyl (DNP), which specifically targets the surface of free virus and viral-infected cells. We show that this leads to simultaneous inhibition of virus release, and immune-mediated elimination of both free virus and virus-infected cells. Intranasal or intraperitoneal administration of a single dose of drug to mice infected with 100x MLD50 virus is shown to eradicate advanced infections from representative strains of both influenza A and B viruses. Since treatments of severe infections remain effective up to three days post lethal inoculation, our approach may successfully treat infections refractory to current therapies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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2,4-Dinitrophenol / administration & dosage
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2,4-Dinitrophenol / chemistry
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2,4-Dinitrophenol / immunology
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Administration, Intranasal
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Animals
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Antibodies / administration & dosage
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Antibodies / immunology
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Antiviral Agents / administration & dosage*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Cell Line
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Cytotoxicity, Immunologic / drug effects
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Drug Delivery Systems
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Humans
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Immunotherapy / methods*
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Influenza A virus / drug effects
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Influenza A virus / enzymology
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Influenza A virus / physiology
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Influenza B virus / drug effects
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Influenza B virus / enzymology
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Influenza B virus / physiology
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Infusions, Parenteral
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Mice
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Mice, Inbred BALB C
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Neuraminidase / antagonists & inhibitors
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Neuraminidase / metabolism
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Orthomyxoviridae Infections / drug therapy*
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Orthomyxoviridae Infections / pathology
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Orthomyxoviridae Infections / virology
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Protein Binding
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Treatment Outcome
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Virus Release / drug effects
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Zanamivir / administration & dosage
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Zanamivir / chemistry
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Zanamivir / pharmacology
Substances
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Antibodies
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Antiviral Agents
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Neuraminidase
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Zanamivir
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2,4-Dinitrophenol