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Last Updated: Sunday, 2 May, 2004, 23:35 GMT 00:35 UK
Push for anti-nerve agent drug
By Paul Rincon
BBC News Online science staff

Emergency services in chemical suits
The molecules could break down deadly agents before they do harm
Molecules that destroy deadly nerve agents could provide the basis of a new type of civilian drug to protect people against a terrorist attack.

The US army is testing the enzymes - called paraoxonases - to see if they could be used to protect troops from exposure during battle.

But Israeli researchers working in the field say any new drug could also have a role in the civil defence setting.

However, the new technology is likely to take some years to develop and test.

The paraoxonases might also have applications as sprays to decontaminate areas and groups of people exposed to nerve agents.

Paraoxonases are a particularly attractive choice as the basis for developing pre-treatment drugs, or prophylactics, because they completely break down organophosphorus nerve agents like sarin, the agent used in the Tokyo underground attack in March 1995.

Ongoing protection

Neither of the current prophylactics in use by the military, or in development, work in this way.

Another anti-nerve agent enzyme known as butyrylcholinesterase works by binding to organophosphates, preventing them from doing any harm. But as the enzymes bind to organophsophorus molecules they are used up.

When people are given things to self-administer they will often overdose in anticipation of an attack
Dr Sally Lievesley
Paraoxonases could break down organophosphates and regenerate, continuing to work even after multiple exposures to nerve agents - so long as the enzymes are present in the bloodstream.

Dr David Lenz, of the US Army Medical Research Institute of Chemical Defense, in Maryland, US, told BBC News Online that the army was to begin testing the paraoxonases to see if they could be turned into prophylactics to be administered to American troops operating in zones at risk of a chemical attack.

"We are trying to develop proteins of human origin that we could administer to people as drugs, as a pre-treatment or prophylactic," Dr Lenz said.

"They would remain in circulation and be capable of destroying toxic, xenobiotic materials in the bloodstream before they could do any harm. So we have an interest in paraoxonase from that aspect."

3D advance

Joel Sussman, Israel Silman, Dan Tawfik and colleagues at the Weizmann Institute in Rehovot, Israel, outlined recently the structure of the paroxonase Pon1 at the first international conference on the paraoxonases in Ann Arbor, US. The structure was determined using the technique of X-ray crystallography.

Paraoxonase Pon1, Nature Structural and Molecular Biology
The paraoxonase Pon1 has unique properties
"Having the 3D structure puts us in a position where we can begin to see how to modify some of the groups in the active site and test if they could work effectively against the more toxic nerve agents," Professor Sussman told BBC News Online.

The researchers believe drugs based on the molecules could eventually be made available to the public.

A paraoxonase prophylactic might work on the same principle as enzyme replacement therapy, used to treat a disorder of the metabolism called Gaucher's disease.

The enzyme could be administered by injection and would remain in the blood for hours or days.

Public control

But the principle of unsupervised use of anti-nerve agent drugs by civilians concerns some experts.

"When people are given things to self-administer they will often overdose in anticipation of an attack," said Dr Sally Lievesley, of UK-based security consultant New Risk.

"You have to have something that's not highly toxic. Under an extreme weapons attack the dose that soldiers have may produce side effects but it's going to keep them alive. You're dealing with a disciplined group.

"But there are different criteria if you're dealing with peacetime populations who may self-dose ahead of time. With the general public you're into a different level of safety."

But Dr Lievesley added that it was not uncommon for military products to have civilian spin-offs.

Insulin experience

"I can't see why it would be different from any other medicine," Professor Silman explained.

"The most difficult thing with all these things is that they have to be compatible with the immune system. But there's nothing impossible about this."

Tokyo underground attack, AP
Commuters on the Tokyo underground were attacked with sarin in 1995
He pointed out that insulin, which could be lethal in overdose, was routinely self-administered by diabetics.

Dr Lievesley said there was a race on to develop prophylactic drugs for use by those in the emergency services who might have to respond to multiple attacks with chemical weapons.

"The difficulty with nerve agents is their rapidity of action," Professor Alistair Hay, a chemical weapons specialist at the University of Leeds, UK, said.

"Organophosphate nerve agents are very fast acting through inhalation. But you might have more leeway with skin penetration.

"You have to have a reasonable residence time in the blood for them to be efficacious. What you need to do is prevent exposure in the first place with good masks, good protective suits and that's where the emphasis needs to be."




SEE ALSO:
Caution urged over bio research
19 Apr 04  |  Health
Better bio-weapons controls urged
19 Jan 04  |  Science/Nature


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