fears grow as H5N1 avian influenza gets closer to the U.K.
An article entitled "Jabs shortage as bird flu threat grows," published on October 16, 2005, on the news.telegraph web site (which also features an article entitled "Donaldson warns: Bird flu could kill 50,000 in UK" published the same day) raises an alarm when it says:
"Emergency plans to deal with a bird flu epidemic were in chaos last night as the deadly virus H5N1 moved closer to Britain.
"Tests which confirm that the virus has travelled thousands of miles from South East Asia to Romania mean that Britain is increasingly at risk."
Tamiflu® is based on a component of the star anise plant/herbal from China
The article is also noteworthy in that it reveals some important information that may have bearing on the ability of the global drugs manufacturing sector to produce sufficient quantities of the anti-viral Tamiflu® in time to help prevent or mitigate the effects of H5N1 avian influenza ("bird flu") in millions of people who may be at risk for contracting this disease.
According to this article:
"Production of Tamiflu, made by the Swiss company Roche, is being hampered by a shortage of star anise, a star-shaped fruit grown in China and the source of shikimic acid from which Tamiflu is made in a year-long process. Ninety per cent of the harvest is already used by Roche."
(Those interested in the relationship between various forms of "star anise" and "anise" can click
here and
here.)
ramping up production of Tamiflu from non-plant sources of shikimic acid
More about this can be found in an October 13, 2005, article on the
consumeraffairs.com web site entitled
"Doctors, Patients Rush to Stockpile Tamiflu--Fear of Avian Flu Sparks Run on Antiviral Medications, where it says:
"Swiss-based Roche says it is working with other manufacturers to begin producing massive quantities of the drug. It is made from an acid produced from the Chinese star anise plant, which is in limited supply because it is grown in only four provinces in China and is harvested between March and May.
"However, Roche says that is has recently developed a way to make the acid, called Shikimic acid, without the plant."
origins and basis of the non-plant production of shikimic acid
Roche's method of making shikimic acid without the plant relies on a method
patented by the "Board of Trustees operating Michigan State University (East Lansing, MI)" which claims "a method for the production of shikimic acid from a carbon source."
According to an article entitled
"Complexity Of Tamiflu Manufacturing May Hamper On Demand Production," published on August 29, 2005, on the
Chemical & Engineering News web site:
"From the sourcing of the raw material to the production of capsules, it takes a full 12 months to make Tamiflu, according to Martin Karpf of Swiss drug giant F. Hoffmann-La Roche’s synthetic and process research group. Manufacture of the oral antiviral, thought to be the most promising weapon against avian influenza currently available, involves time-consuming routes to the starting material and steps that require potentially hazardous azide chemistry.
"The 10-step commercial route uses the natural product (–)-shikimic acid as a starting material….
"Initially, research quantities of (–)-shikimic acid cost more than $50 per gram, Karpf notes. This precursor “simply was not available on the world market in large amounts,” he says.
"Needing to obtain a cheaper and more reliable supply of the starting material, Roche turned to Michigan State University chemist
John W. Frost, whose lab had developed a strain of Eschericia coli that overproduces (–)-shikimic acid when fed glucose. Within a year and a half, Roche had figured out how to grow these bacteria on a commercial scale and determined how to extract and purify the (–)-shikimic acid."
One problem facing producers of Tamiflu is reliance on "three potentially toxic and explosive azide intermediates." But, according to this article, "Frost has begun to develop a microbial synthesis of aminoshikimic acid, which could reduce the need for azide chemistry if used as a starting material (
Org. Lett 2004,
6, 1585). So far, however, none of these alternatives has measured up to the commercial route in terms of cost and efficiency."
You can read this article about the production of Tamiflu®, the factors that impede its rapid manufacture, and steps being taken to overcome these obstacles, in its entirety, by clicking
here.
pre-2000 research into the biosynthesis of shikimic acid
Of related interest may be
"Analysis and modelling of shikimic acid metabolism in Escherichia coli," by Mikael Johansson of the Department of Chemical Engineering II, Lund University, Lund, Sweden, which reports that:
"it has recently been found that shikimate [L-shikimic acid] is a good building block for the anti-influenza drug GS-4104 (2,3). Earlier it has been isolated from the plant
Illicium [star anise] (4). However it can also be produced fermentively, using genetically modified strains of
E. coli."
2.
Rohloff J.C. et al Practical total synthesis of the Anti-Influenza drug GS-4101, Journal of organic chemistry 1998(63) p 4545-4550.
3.
Kim C.U., et al Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction on the enzyme active site: Design, synthesis and structural analysis of carbocylic sialic acid analogues with potent anti-influenza activity, Journal of the american chemical society 1997 (119) p 681-690.
4.
Draths K.M., Knop D.R., Frost J.W. Shikimic acid and quinoc acid: Replacing isolation from plant sources with recominant microbial biocatalysis. Journal of American chemical society 1999 (121) p 1603-1604.
As indicated by the dates of the references cited in this paragraph, the basic discoveries involved in the biosynthesis of shikimic acid took place between 1997 and 1999, roughly contemporary with the first recorded outbreak of H5N1 avian influenza in humans.
According to the United Nations' World Health Organization, "The first recorded outbreak of H5N1 infection in humans occurred in Hong Kong in 1997, when 18 persons developed serious disease and six died."
other possible plant sources of shikimic acid
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