Abstract
Influenza therapy with a single targeted compound is often limited in efficacy due to the rapidly developed drug resistance. Moreover, the uncontrolled virus-induced cytokines could cause the high mortality of human infected by H5N1 avian influenza virus. In this study, we explored the novel dual-targeted bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents. In particular, the caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1) and ZA-7-CA-amide (7) showed simultaneous inhibition of influenza virus neuraminidase and suppression of pro-inflammatory cytokines. These ZA conjugates provided remarkable protection of cells and mice against influenza infections. Intranasal administration of low dosage (<1.2 μmol/kg/day) of ZA conjugates exhibited much greater effect than the combination therapy with ZA and the anti-inflammatory agents in protection of the lethally infected mice by H1N1 or H5N1 influenza viruses.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Caffeic Acids / chemical synthesis*
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Caffeic Acids / pharmacology
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Cell Line
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Dogs
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Female
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Influenza A Virus, H1N1 Subtype
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Influenza A Virus, H5N1 Subtype
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Interferon-gamma / blood
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Interleukin-6 / blood
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Lipopolysaccharides / pharmacology
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Mice
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Mice, Inbred BALB C
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Neuraminidase / antagonists & inhibitors
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Orthomyxoviridae Infections / drug therapy
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Orthomyxoviridae Infections / virology
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / blood
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Zanamivir / analogs & derivatives*
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Zanamivir / chemical synthesis*
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Zanamivir / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antiviral Agents
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Caffeic Acids
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Interleukin-6
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Lipopolysaccharides
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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Neuraminidase
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Zanamivir