Enhanced anti-influenza agents conjugated with anti-inflammatory activity.

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.

• Authors: Kung-Cheng Liu, Jim-Min Fang, Jia-Tsrong Jan, Ting-Jen R Cheng, Shi-Yun Wang, Shi-Ting Yang, Yih-Shyun E Cheng, Chi-Huey Wong
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 19 Pg. 8493-501 (Oct 11 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22963087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antiviral Agents
• Caffeic Acids
• Interleukin-6
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• Neuraminidase
• Zanamivir

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Caffeic Acids (chemical synthesis, pharmacology)
• Cell Line
• Dogs
• Female
• Influenza A Virus, H1N1 Subtype
• Influenza A Virus, H5N1 Subtype
• Interferon-gamma (blood)
• Interleukin-6 (blood)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred BALB C
• Neuraminidase (antagonists & inhibitors)
• Orthomyxoviridae Infections (drug therapy, virology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Tumor Necrosis Factor-alpha (blood)
• Zanamivir (analogs & derivatives, chemical synthesis, pharmacology)