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Last Updated: Friday, 5 May 2006, 21:51 GMT 22:51 UK
Scientist seeks quicker Tamiflu
By Roland Pease
BBC science correspondent

Tamiflu pills
World governments are building up stocks of Tamiflu
A Nobel laureate has devised a new way to make the anti-flu drug Tamiflu that is simpler and quicker than the process employed to produce it right now.

Elias Corey's hope is that his novel approach will mean the drug is cheaper to manufacture and more plentiful.

It took him just a few minutes to work out the method while relaxing at home one weekend, the US researcher says.

Tamiflu is the anti-viral drug of choice in the world preparations for possible pandemic flu.

The Swiss manufacturer Roche has given the World Health Organization five million courses of treatment to help stamp out any incipient outbreak of the disease at source.

And with the help of global partners, the company promises to be producing four hundred million courses a year by 2007.

Critical differences

However, build-up is limited by the fact that the starting material for the production cycle is a compound extracted from the plant star anise, grown in mountain provinces in southwest China.

It is not that the compound, called shikimic acid, comes with any special anti-viral properties of its own; but rather at its heart is a ring of carbon molecules that makes a very particular template on which the rest of the drug can be built.

I happened to be at home one Saturday morning, and I took some time out to think about the problem, and within a few minutes I came up with some ideas for solving it
Prof Elias Corey
Starting with a simpler framework would destroy the chance of making the pure functioning drug.

Star anise has to be harvested once a year, and Tamiflu production is now taking up most of the crop. Professor Corey read in the papers of the limit this put on production capacity, and he began to think about ways around the problem.

Corey won the Nobel Prize for Chemistry in 1990 for his successes in devising lab-bench approaches to synthesising natural compounds.

Many of these have similar or even greater structural complexity than shikimic acid, where interchanging two bonds, while leaving the chemical formula the same, will utterly change the properties.

Thinking time

An old approach in chemistry has been to make mixtures of the useful and useless forms of complex molecules, and then to separate them later - a wasteful and time-consuming process.

Professor Corey was a pioneer of techniques for forcing simple chemicals into pre-determined arrangements against their natural habit.

He saw Roche's problems and was sure he could come up with a solution. He did; and it didn't take long.

"I happened to be at home one Saturday morning, and I took some time out to think about the problem, and within a few minutes I came up with some ideas for solving it," he told the BBC's Science in Action programme.

"I called some of my students, and said, 'would you like to try something that could save many lives', and they agreed."

Just eight weeks later, the whole process had been worked through and refined, and the product compared with genuine Tamiflu. The recipe is described in the online edition of the Journal of the American Chemical Society.

Chemical 'marriage'

Corey's approach takes eleven separate chemical steps in all - but few drugs can be made in a single leap.

Components may have to be added one by one; to take a DIY analogy, there is the chemist's equivalent of surface preparation and laying down of masking tape to be done. Even Roche's approach - already improved twice - takes 10 steps.

But the starting materials are exceedingly simple - they are the feedstock for synthetic rubber, Plexiglass, and other plastics, and cost just pennies per kilo, says Professor Corey.

The secret is in a catalyst developed in the Corey lab. A kind of chemical marriage broker, it efficiently unites the raw ingredients to make the same kind of precision carbon framework found in shikimic acid.

"It provides a specific three-dimensional arrangement which serves as a platform for developing all of the features of the final drug," he explains.

Of course, transferring a process from the sheltered environment of the university lab to the reality of an industrial site is not easy, and Professor Corey accepts that. But the catalyst that makes the whole approach possible is almost identical to one already widely used to make the asthma treatment Advair - one of GlaxoSmithKline's top selling products.

Professor Corey's approach also avoids two steps in the current method that involve highly explosive compounds.

These have to be outsourced to specialist companies, slowing down manufacture, and can only be done using limited quantities at a time for safety's sake.

However, a new process would require extra investment in chemical equipment; and any drug produced in the Corey fashion would have to be separately licensed by the medical authorities.

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