title: 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.affiliation: Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Kung-Cheng
authors.initials: KC
authors.lastname: Liu
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.forename: Jia-Tsrong
authors.initials: JT
authors.lastname: Jan
authors.forename: Ting-Jen R
authors.initials: TJ
authors.lastname: Cheng
authors.forename: Shi-Yun
authors.initials: SY
authors.lastname: Wang
authors.forename: Shi-Ting
authors.initials: ST
authors.lastname: Yang
authors.forename: Yih-Shyun E
authors.initials: YS
authors.lastname: Cheng
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002109:Caffeic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype; D053124:Influenza A Virus, H5N1 Subtype; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D002109:Caffeic Acids; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D009439:Neuraminidase; D053243:Zanamivir