Sat, Jul 12, 2008 page2

• Institute advances flu drug manufacturing

  • By Meggie Lu / STAFF REPORTER
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  The Academia Sinica has discovered a safer and more efficient method of producing Tamiphosphor, a drug candidate used to combat influenza, including both bird flu and the common flu, it announced yesterday.

  The method can also be applied in manufacturing Tamiflu, the most common drug on the market used to treat the disease, said Fang Jim-min (方俊民), a research fellow at the academy’s Genomics Research Center.

  The breakthrough was published yesterday as a “hot paper” in Angewandte Chemie, a highly influential journal in the field of chemistry.

  “Although the manufacturing procedure [by Roche pharmaceutical company] for Tamiflu is relatively effective, the process has two shortcomings,” Fang said.

  First, Tamiflu manufacturing requires shikimic acid, which is extracted from star anise, a natural herb.

  “However, the purity of shikimic acid is difficult to attain in large quantities,” he said.

  Second, potentially explosive azide reagents and intermediates are used during production, which gives the process an element of precariousness and danger, Fang said.

  The center has been working on an alternative method to develop a better drug in a safer way since 2005, Fang said.

  In September it announced the development of Tamiphosphor, which in lab mice proved to be more effective than Tamiflu, said Shie Jiun-jie (謝俊結), another researcher at the center.

  “While Tamiflu and Tamiphosphor inhibit the activity of neuraminidase, an enzyme that is essential in the replication process of influenza viruses H5N1 and H1N1, Tamiphosphor was found to be more effective in enzyme inhibition and yielded higher survival and recovery rates in infected mice,” Shie said.

  However, at the time Tamiphosphor’s 45-day, 19-step manufacturing process made it far from being commercially viable, Shie said.

  Working to shorten the production lead time, the team employed an innovative “retrosynthetic method,” Shie said.

  “After analyzing the compound structures of both Tamiflu and Tamiphosphor, we backtracked step by step to find the string of precursor compounds and eventually deduced a number of starting compounds that would eventually yield the drugs,” Shie said.

  Several compounds were identified, Shie said, adding: “Taking cost into consideration, we chose bromobenzene, a common and inexpensive chemical, as our raw material.”

  Using bromobenzene, chemical functional groups are added step by step; in the end, the bromine atom is either converted into carboxyl to make Tamiflu, or phosphonate to make Tamiphosphor, he said.

  “Not only has the production process been cut to 11 steps and two weeks, the new method eliminates potentially explosive compounds and is much safer,” Shie said.

  With a simpler and shorter production process, the manufacturing yield has doubled, boosting its commercial potential, Fang said.

  Although it would take at least five to 10 years more for Tamiphospor to hit the market, “if it makes it that far,” Fang said that the team planned to continue with its research.

  “We are already in talks with several pharmaceutical companies about the next steps for this drug candidate,” he said.
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