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Tamiphosphor: A new orally active enzyme inhibitor against human and bird flu viruses is developed

TamiphosphorDiagram
Survival rate of mice inoculated with 10 MLD50 of A/WSN/33 (H1N1) influenza virus and treated at a drug dosage of 1 mg/kg/day.
The SARS outbreak back in 2003 alerted the world enormously due to the pandemic effect has proved to be above boundaries and beyond existing medical awareness. A research team at the Genomics Research Center of Academia Sinica has been developing vaccines and small molecules as new drug candidates targeting threats of various viruses. Their newest breakthrough is a promising drug candidate that can fight against bird flu and human influenza.

The wide-spread of highly pathogenic avian flu in many countries and the reported human infections have raised a serious concern about a global pandemic influenza. It is feared that sooner or later the virus will morph into a new kind that will be transmissible among humans.

At present, four drugs are approved for influenza prevention and treatment. Amantadine and Rimantadine act as the M2 ion channel blockers; however, their use is limited due to the problem of severe side effects and drug resistance. Tamiflu and Relenza inhibit the activity of influenza viral neuraminidase. Relenza must be applied by nasal spray, whereas Tamiflu is a popular anti-influenza drug for oral administration. Nonetheless, the recent reports on the drug resistant avian flu infections and the side effects in children receiving Tamiflu treatments suggest that new neuraminidase inhibitors are in desperate need.

The new drug Tamiphosphor reported by the team can be taken orally and proves to be far more powerful than Tamiflu. It is potent than Tamiflu by 19- and 7-folds, respectively, in the enzyme inhibition and cell-based anti-flu assays. Tamiphosphor is a compound of cyclohexene phosphonate, which is a structural congener of Tamiflu. By replacing of the carboxyl group in Tamiflu with the phosphonate group, Tamiphosphor provides more extensive hydrogen bonding interactions with the key tri-arginine residues in the neuraminidase active site, and thus corresponds to higher affinity in the enzyme inhibition and better anti-flu activity.

An exciting and surprising observation is that Tamiphosphor and its diethyl ester are orally bioavailable in protecting mice against lethal challenge with influenza viruses. By comparison of the survival rate and mean survival time of mice, both Tamiphosphor and its diethyl ester are more effective than Tamiflu against H1N1 human influenza virus and at least equally effective against recombinant H5N1 (NIBRG14) virus. For example, the mice inoculated with 10 MLD50 of influenza virus A/WSN/33 (H1N1) all die at day 5. On treatment with Tamiflu (1.0 mg per kg of body weight per day by oral gavage twice daily for 5 days), 40% mice survive at day 7, but all die at day 14. Overall, with the Tamiphosphor treatment, 50% of the mice survived at day 14 after a similar treatment.

The study of Tamiphosphor was directed by Dr. Chi-Huey Wong, President of Academia Sinica and Dr. Jim-Min Fang, a professor at National Taiwan University with a joint appointment at the Genomics Research Center. The expedient synthesis of Tamiphosphor from a readily available sugar, D-xylose, is carried out by Dr. Jiun-Jie Shie, a postdoctoral research fellow in Academia Sinica. This study is published in current issue of Journal of American Chemical Society (web release on September 12, 2007).

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