tetano
Editor, Senior Moderator
Jim-Min Fang , Kung-Cheng Liu , Jia-Tsrong Jan , Ting-Jen R. Cheng , Shi-Yun Wang , Shi-Ting Yang , Yih-Shyun E. Cheng , and Chi-Huey Wong
J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/jm3009844
Publication Date (Web): September 10, 2012
Copyright ? 2012 American Chemical Society
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.
http://pubs.acs.org/doi/abs/10.1021/jm3009844
J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/jm3009844
Publication Date (Web): September 10, 2012
Copyright ? 2012 American Chemical Society
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.
http://pubs.acs.org/doi/abs/10.1021/jm3009844