SARS STOCKS

[Rocketred]

U.S. Army testing finds drugs that may stop SARS
Friday, May 2, 2003 By DANIEL Q. HANEY AP Medical Editor
FORT DETRICK, Md. (AP) - The first strong evidence that medicine will eventually defeat the SARS virus has come to light in recent days at the Army's biodefense labs, where the world's most intensive and systematic search for a cure is going on around the clock.


Scientists are concentrating on antiviral drugs already in drugstores, hoping to find something that will quickly help people dying from the new respiratory disease.


While most of these medicines have failed so far, one category has popped out as promising _ the natural infection-fighting protein interferon.


At the same time, the scientists have tested a few experimental compounds that seem especially intriguing, based on what they know about the internal mechanics of the SARS virus. The potentially pivotal result: Drugs called protease inhibitors, chemical cousins of the medicines that defeated AIDS, can stop the SARS virus cold.


These hits, as the scientists call them, are just the first step in finding possible treatments for SARS. All the tests are done in lab dishes, and treatments that work spectacularly on that level can be disappointing in people. In the months to come, they expect to test at least 100,000 compounds, perhaps even 500,000.


Nevertheless, the scientists are exultant that their search has so rapidly turned up leads to take into more elaborate experiments.


"It's a pretty big deal. We are excited about it," says Peter Jahrling, senior research scientist at the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick.


USAMRIID's usual work is finding defenses to the contagion troops can encounter, intentionally or by chance, anywhere on the planet. These scientists' expertise in handling odd, poorly understood and dangerous bugs made them a natural choice for drug screening when severe acute respiratory syndrome emerged in Asia as a never-before-seen form of pneumonia.


John Huggins, who is in charge of antiviral drugs, went to work methodically infecting living cells with the SARS virus to see if something, anything, will keep the cells alive.


About 20 people work at Huggins' level 3 biosafety lab _ one step down from the most secure _ housed in a blank-walled World War II relic across the lawn from USAMRIID's headquarters. In these beginning days, they are testing any medicine that makes sense _ and some with no biological plausibility at all _ in search of quick hits.


"Unfortunately, it is far better to be systematic than it is to be smart in these early steps," says Huggins. "Trying to guess and blindly going where logic leads you is dangerous when you know so little."


By serendipity, they hope, something already in routine use will cure SARS. But of the several dozen tested so far, mostly standard drugs for HIV and herpes, only interferon has shown promise.


Interferon is one of the body's general purpose virus-stoppers. It comes into play before the immune system gears up production of more precisely targeted antibodies.


Duplicated through genetic engineering, interferon is available commercially in several different forms. The Army lab found that a variety called interferon beta blocks the SARS virus in the lab dish, although it takes 10 times more than would ordinarily be given to a patient. Still, experts say smaller doses might be effective inside the human body.


While interferon appears to have the best chance of quickly becoming a treatment for the disease, Huggins says, extra testing is necessary to make sure it does more good than harm.


Because the respiratory disease is brand new, no one knows exactly why it makes people so sick, in some cases destroying their lungs. Certainly, the virus itself is capable of great damage. But in some infections, the body's own over-the-top counterattack _ including vast production of interferon _ can be as bad as the bug itself.


So before interferon becomes a SARS treatment, doctors will have to be sure patients are not already making more than enough interferon of their own.


However, Dr. Frederick Hayden, a respiratory virus expert at the University of Virginia, notes that when the flu causes pneumonia, the body produces too little interferon to fight back effectively, so the Army lab results "raise the possibility of using interferon either for prevention or for therapy of SARS."


Experts are also encouraged to learn that drugs called cysteine protease inhibitors can stop the virus by jamming one of the enzymes it needs to make new copies of itself. Jahrling says the lab has tested 19 of them, and six work well. "They clearly inhibit replication of the virus and do so at concentrations that are not toxic to the cells."


The drugs were all created by pharmaceutical firms to treat or ward off colds caused by the rhinoviruses, but none of the six have been given to people. Because of similarities between the various respiratory viruses, scientists have hoped from the start that medicines aimed at colds and flu will turn out to be good for the SARS virus, too.


Even if these particular ones are not perfect, something like them might be. So the lab will gather up lots of closely related compounds that were abandoned by pharmaceutical companies along the way.


If interferon and other on-the-market medicines fail, the conquest of SARS will almost certainly be a slow business. Developers will have to work their meticulous way through each plodding step, proving that the medicine helps infected lab animals, that it is safe enough for people and ultimately that it cures the sick, first in experiments on a few, then on many.


Because of SARS' urgency, drug development is likely to move at top speed, and Hayden predicts that a medicine such as a protease inhibitor could be ready for testing on people within a year.


Meanwhile, Huggins' lab goes nonstop. It thoroughly tests about 25 drugs at a time and must wait three days for an answer. Soon, the team expects to scale up testing to 100 at once.


Every drug gets a pair of 4-by-6-inch trays, each divided into 96 separate compartments with varying concentrations of the medicine plus a layer of monkey cells. The scientists add enough SARS virus to infect one in 1,000 cells.


As bad as the virus is for human lungs, it behaves obediently in the lab, growing robustly in these cell cultures. Under 40-times magnification, its destructive punch is obvious. The usual brick-like rows of cells puff up as the virus takes control. Some of them literally explode, leaving holes.


If the drug works, the virus does not spread. Cells stay healthy. To see how they fare, scientists douse them with a dye that is absorbed by healthy cells. If they soak up a lot, they are doing fine, and the drug is effective.


The lab is working with the National Institute of Allergy and Infectious Diseases and the Food and Drug Administration to round up anything that might work. They plan to test everything, within reason, that is offered by drug developers or anyone else with a good idea.


"We have been pleasantly amazed by the number of pharmaceutical firms, large and small, as well as academic investigators who have offered compounds for screening," says Catherine Laughlin, virology chief at the infectious disease institute.


The government is not simply waiting for drugs to show up in the mail, either. The FDA is coaxing drug companies to submit possible antiviral drugs that the agency knows they are working on or may even have discarded.


To be sure nothing is missed, the Army lab will eventually try every category of medicine sold around the world, no matter what it is intended for. It will screen all 880 drugs in a collection of chemically unique medicines maintained by Prestwick Chemical Inc.


Much of the testing, though, will not involve the exhaustive screening given to the top prospects. Instead, the labs will load five drugs into each of the compartments on its trays, then go back and figure out which one was responsible if they get a hit.


Already, the labs have screened 3,000 compounds with this quick run-through. And one of them, submitted by a small pharmaceutical company, stopped the virus. The next step will be to test the five separately to see which one did it.


Some drug makers are anxious to get their compounds into the testing queue. For instance, AVI BioPharma has just finished crafting a possible drug intended to disable the virus' genes and is shipping it off to the Army lab.


Testing there "lends tremendous credibility," says Denis Burger, the firm's chief executive. "There is not another facility anywhere that matches this in terms of the muscle they can throw at it."


But until they understand more about what is likely to work, the Army scientists will entertain just about any idea. In fact, they say a high point of their day is looking at the SARS cures that well-meaning people propose out of the blue.


Dried broccoli is Huggins' favorite. Elderberry syrup has come in at least four times. "Eucalyptus oil!" Jahrling says, skimming his e-mail.


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EDITOR'S NOTE: Medical Editor Daniel Q. Haney is a special correspondent for The Associated Press.


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On the Net:


NIAID site: http://www.niaid.nih.gov/factsheets/sars.htm