Liu, K.-C.K.-C.LiuJIM-MIN FANGJan, J.-T.J.-T.JanCheng, T.-J.R.T.-J.R.ChengWang, S.-Y.S.-Y.WangYang, S.-T.S.-T.YangCheng, Y.-S.E.Y.-S.E.ChengWong, C.-H.C.-H.Wong2018-09-102018-09-102012http://www.scopus.com/inward/record.url?eid=2-s2.0-84867389246&partnerID=MN8TOARShttp://scholars.lib.ntu.edu.tw/handle/123456789/371480Influenza 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. ? 2012 American Chemical Society.[SDGs]SDG3antiinflammatory agent; caffeic acid; virus sialidase; zanamivir; animal experiment; animal model; antiinflammatory activity; article; enzyme inhibition; influenza A (H1N1); influenza A (H5N1); Influenza virus A H1N1; Influenza virus A H5N1; mouse; nonhuman; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Caffeic Acids; Cell Line; Dogs; Female; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Interferon-gamma; Interleukin-6; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Neuraminidase; Orthomyxoviridae Infections; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tumor Necrosis Factor-alpha; Zanamivirjournal article10.1021/jm30098442-s2.0-84867389246WOS:000309643500026