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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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In the Pipeline

« The Flu Plan, Part One: Vaccines | Main | Merck Off the Mat »

November 2, 2005

The Flu Plan, Part Two: Antiviral Drugs

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Posted by Derek

In the first post below, I said that we would be in big trouble if we had to rely on a vaccine for all of our protection against a flu pandemic. The problem is, if we're relying on antiviral drugs, we're in even worse shape. (See my post on this from last March.)

Right now, the only drugs likely to do much of anything against an influenza pandemic are the neuraminidase inhibitors like Tamiflu and Relenza. But the problem is, these drugs really have to be taken early in the course of the infection to be most effective. By the time many people realize that they have the flu, it may be too late to do much about it.

One way to get around that problem would be to take the drugs prophylactically, but that has two serious disadvantages. For one thing, this route might well lead to a quicker development of resistant viral strains, which is something that we already know can happen. And for another, it would burn through huge amounts of drug, and we don't happen to have huge amounts of either one.

Why is that? Well, for one thing, neither compound was selling very well until recently. The companies involved have never had to ramp up production to the levels that people are talking about now. It's doable, but it won't be fun. The ten-step Roche synthetic route to Tamiflu uses some azide chemistry, which is potentially toxic and explosive, but it's nothing that a good bunch of industrial chemists can't handle. (It helps, for example, that India's Cipla already has experience making AZT, because that relies on similar chemistry). But any ten-step route is not going to be trivial to implement if you've never done it before, azide or no azide.

A bigger problem is that these drugs have syntheses from a starting material called shikimic acid. That's a component of an important metabolic pathway in plants. (It's important enough that the well-known herbicide Roundup works by shutting it down). Shikimic acid is found in small quantities in a lot of plant species, but star anise, a spice used in Chinese cooking, has a lot of it. (If you'd like to extract some from any star anise you have in your kitchen, here's how). Roche already has a network of suppliers in China, and the generic companies who plan to produce the drug are having a hard time sourcing the shikimate. It can also be produced by fermentation, which Roche uses for some of its supply, but that's an even more specialized process.

All in all, I think it's prudent to stockpile these drugs, although I'm not sure, for the reasons given above, where the US government is going to find the quantities it's looking for. But even if we can pile the stuff up to the rafters, we have to be ready for the possibility that these drugs may or may not do us much good. I see that I've ended both of these posts on the same note. . .

Comments (7) + TrackBacks (1) | Category: Infectious Diseases


1. rob on November 3, 2005 12:16 AM writes...

The CDC's influenza advisory panel has been pushing certification of cell culture for flu vaccine for the last 3 yrs. I remember Peter Pelese, a virology professor from Mt. Sinai, pounding the table for it in spring of 2003, but the other committee members had concerns about safety and efficacy.

It was those arguments that led to NIAID's contracts for vaccine development by Chiron, Sanofi-Aventis, and most recently Medimmune.

Btw, very nice blog you have here. I dabbled in an organic chem lab group when i was in undergrad. it was way too hard.

Permalink to Comment

2. Lars on November 3, 2005 4:15 AM writes...

Sourcing enough starting materials and sourcing the drug itself is a huge problem if stock-piling turns out to be a viable option. Would be nice to see the same kind of spirit and synergy that companies like Merck, Pfizer and Squibb showed during the later years of WWII when they collaborated to produce up towards 20 billion dosage units of penecillin G a month to aid the war effort. Naturally they benefited financially from this, but one can't help to think it was more for the greater good. Has "chivalry" gone lost in the pharmaceutical giants of today?

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3. Klug on November 3, 2005 9:16 AM writes...

You know, shikimic acid doesn't seem SO hard to synthesize. I fully realize that it would add that much more to the overall synthesis, but it just seems like you should be able to tackle it from a total synthesis perspective. [Then again, a quick and dirty search only reveals 2 total syntheses and only one that is fully chiral.] It is obviously a cost and time issue.

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4. Derek Lowe on November 3, 2005 10:27 AM writes...

Time and cost, absolutely. Synthesizing chiral compounds de novo is an absolute last resort on the pharmaceutical manufacturing scale, and the more chiral centers involved, the worse the problem is. It's far, far better to let living systems do the work for you if at all possible.

I'm sure if shikimic acid somehow became necessary to the survival of millions of people (and I really don't see how that's going to be the case), then we'd bang it out by any means possible, and hang the expense. But we're nowhere near that stage. I need to write a post about the WWII efforts on beta-lactams.

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5. Jessica on November 3, 2005 7:06 PM writes...

I think this new flu plan is a waste of time and money. These companies give alot of money to the Bush campaign and his croonies. This is a great scare tactic to use tax payer funds on worthless flu vaccinnes.

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6. nick on November 4, 2005 2:19 PM writes...

Hi there Derek, it's been awhile.
Did you see the article showing one can boost Tamiflu activity by inhibiting kidney function? Apparently people have been doing this for longer than either of us has been alive. However, we'd still need more than we can produce and viruses are just as capable of developing resistance as bacteria (well, in fact they're MORE capable).

Permalink to Comment

7. kevin on November 8, 2005 8:00 PM writes...

So when the bird flu crosses with SARS, i that when we really need to worry?

Permalink to Comment


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