Giuseppe
Emeritus
Researchers unveil drug breakthrough
Publication Date：07/17/2008 - Section：Front Page - By Edwin Hsiao
Researchers at the Genomics Research Center of Academia Sinica, Taiwan's foremost academic institution, announced July 11 they had discovered a safer and more efficient method of producing Tamiphosphor, an experimental drug used to treat human and bird-flu viruses.
The development of Tamiphosphor--which began at the GRC in 2005--was first reported to the public Sept. 27, 2007.
Academia Sinica President Wong Chi-huey directed the study of this medicine, and Fang Jim-min, a National Taiwan University chemistry professor with a joint appointment at the Genomics Research Center, led the research team. Shie Jiun-jie, a postdoctoral research fellow at Academia Sinica, was responsible for conducting the experiments.
The breakthrough was reported in a paper titled "A Concise and Flexible Synthesis of the Potent Anti-Influenza Agents Tamiflu and Tamiphosphor," co-authored by Wong, Fang and Shie, and published in "Angewandte Chemie"--a German-based international journal in the field of chemistry.
The journal's editors have recommended the research as a "hot paper" for timely publication.
Applying a retrosynthetic approach to analyze the chemical structures of Tamiphosphor and Tamiflu, a Swiss-made anti-influenza drug used to combat avian flu, the GRC team substituted xylose for bromobenzene as a starting material, and then added chemical functional groups step by step to complete the synthesis.
According to Shie, the result was an innovative procedure, in which the bromine atom is converted to carboxyl or phosphonate groups at the later stage: a method that can be used to produce Tamiflu as well as Tamiphosphor.
"The first process of Tamiphosphor synthesis took us one and a half months and 19 steps," Shie said.
"The new approach has eight fewer steps and took us only two weeks to complete. This makes the total process much easier and far more economically viable," he added.
GRC Team leader Fang explained that while there are several pharmaceutical companies willing to invest in the development of the new drug, it would take at least five to 10 years for Tamiphosphor to hit the market.
According to Fang, Tamiphosphor, like Tamiflu, can be taken orally, and functions as an inhibitor in the neuraminidase active site of influenza viruses.
But Tamiphosphor is more effective due to its higher level of enzyme inhibition.
Mice infected with H5N1/H1N1 viruses showed higher rates of survival and faster recovery times when treated with the GRC's drug as compared to those that used Tamiflu.
Academia Sinica pointed out that currently there are four kinds of drugs that can prevent or treat influenza.
Amantadine and Rimantadine are less popular and can result in side effects ranging from seizures (in older patients) to insomnia and vertigo.
Tamiflu and Relenza are more widely used worldwide, but after receiving reports of patients experiencing delirium, psychosis and hallucinations, the U.S. Food and Drug Administration recommended that both drugs carry warnings about possible side effects.
In addition, Tamiflu--which is more commonly used in Japan than the United States--was suspected in March 2007 of causing several teenage patients in Tokyo to suffer from mental disorders and hallucinations.
The manufacturer, Switzerland-based F. Hoffman-La Roche Ltd., denied the accusation.
Suggesting a reason why Tamiflu may cause side effects, Fang explained that manufacture of the drug begins by extracting shikimic acid from star aniseed--a licorice-flavored spice that is part of Chinese cuisine's five-spice powder.
"Obtaining pure shikimic acid may be problematic," he said.
A drawback of large-scale shikimic acid synthesis lies in the manipulation of potentially explosive azide reagents, like sodium azide, and intermediates during production.
These give the process an element of precariousness and danger, Fang noted.
The team has applied for a patent for its new synthesis method and is working with local organizations to initiate toxicology tests and preclinical pharmacokinetic studies before eventual mass production.
"We hope we can eventually provide locally manufactured drugs, like Tamiphosphor, to protect Taiwan from bird-flu and human-influenza pandemics and cure patients who have already been infected with viruses," Fang concluded.
Write to Edwin Hsiao at edwinhsiao@mail.gio.gov.tw
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http://taiwanjournal.nat.gov.tw/ct.asp?CtNode=122&xItem=44616
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Publication Date：07/17/2008 - Section：Front Page - By Edwin Hsiao
Researchers at the Genomics Research Center of Academia Sinica, Taiwan's foremost academic institution, announced July 11 they had discovered a safer and more efficient method of producing Tamiphosphor, an experimental drug used to treat human and bird-flu viruses.
The development of Tamiphosphor--which began at the GRC in 2005--was first reported to the public Sept. 27, 2007.
Academia Sinica President Wong Chi-huey directed the study of this medicine, and Fang Jim-min, a National Taiwan University chemistry professor with a joint appointment at the Genomics Research Center, led the research team. Shie Jiun-jie, a postdoctoral research fellow at Academia Sinica, was responsible for conducting the experiments.
The breakthrough was reported in a paper titled "A Concise and Flexible Synthesis of the Potent Anti-Influenza Agents Tamiflu and Tamiphosphor," co-authored by Wong, Fang and Shie, and published in "Angewandte Chemie"--a German-based international journal in the field of chemistry.
The journal's editors have recommended the research as a "hot paper" for timely publication.
Applying a retrosynthetic approach to analyze the chemical structures of Tamiphosphor and Tamiflu, a Swiss-made anti-influenza drug used to combat avian flu, the GRC team substituted xylose for bromobenzene as a starting material, and then added chemical functional groups step by step to complete the synthesis.
According to Shie, the result was an innovative procedure, in which the bromine atom is converted to carboxyl or phosphonate groups at the later stage: a method that can be used to produce Tamiflu as well as Tamiphosphor.
"The first process of Tamiphosphor synthesis took us one and a half months and 19 steps," Shie said.
"The new approach has eight fewer steps and took us only two weeks to complete. This makes the total process much easier and far more economically viable," he added.
GRC Team leader Fang explained that while there are several pharmaceutical companies willing to invest in the development of the new drug, it would take at least five to 10 years for Tamiphosphor to hit the market.
According to Fang, Tamiphosphor, like Tamiflu, can be taken orally, and functions as an inhibitor in the neuraminidase active site of influenza viruses.
But Tamiphosphor is more effective due to its higher level of enzyme inhibition.
Mice infected with H5N1/H1N1 viruses showed higher rates of survival and faster recovery times when treated with the GRC's drug as compared to those that used Tamiflu.
Academia Sinica pointed out that currently there are four kinds of drugs that can prevent or treat influenza.
Amantadine and Rimantadine are less popular and can result in side effects ranging from seizures (in older patients) to insomnia and vertigo.
Tamiflu and Relenza are more widely used worldwide, but after receiving reports of patients experiencing delirium, psychosis and hallucinations, the U.S. Food and Drug Administration recommended that both drugs carry warnings about possible side effects.
In addition, Tamiflu--which is more commonly used in Japan than the United States--was suspected in March 2007 of causing several teenage patients in Tokyo to suffer from mental disorders and hallucinations.
The manufacturer, Switzerland-based F. Hoffman-La Roche Ltd., denied the accusation.
Suggesting a reason why Tamiflu may cause side effects, Fang explained that manufacture of the drug begins by extracting shikimic acid from star aniseed--a licorice-flavored spice that is part of Chinese cuisine's five-spice powder.
"Obtaining pure shikimic acid may be problematic," he said.
A drawback of large-scale shikimic acid synthesis lies in the manipulation of potentially explosive azide reagents, like sodium azide, and intermediates during production.
These give the process an element of precariousness and danger, Fang noted.
The team has applied for a patent for its new synthesis method and is working with local organizations to initiate toxicology tests and preclinical pharmacokinetic studies before eventual mass production.
"We hope we can eventually provide locally manufactured drugs, like Tamiphosphor, to protect Taiwan from bird-flu and human-influenza pandemics and cure patients who have already been infected with viruses," Fang concluded.
Write to Edwin Hsiao at edwinhsiao@mail.gio.gov.tw
-
http://taiwanjournal.nat.gov.tw/ct.asp?CtNode=122&xItem=44616
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