BOSTON, May 19, 2003 (United Press International via COMTEX) -- Scientists said Monday they have discovered how smallpox exerts its virulence, a finding that could lead to medications to fight off the deadly virus as well as treat side effects of the vaccine.

Currently, there is no treatment for smallpox, which can be fatal in about a third of those infected by it, and the only way to prevent infection is with the vaccine that can cause severe reactions in some people, including death.

Researchers at the Massachusetts Institute of Technology found evidence indicating the lethality of the smallpox virus depends on a protein that binds to a rare form of DNA known as Z-DNA. A compound that inhibits or blocks this protein could in turn prevent the virus from causing infection and death.

In addition, a drug that blocks this protein "could be a treatment for smallpox but also could be a treatment for people who have bad reactions to smallpox vaccinations," Ky Lowenhaupt, a research scientist at MIT and a co-author of the study, told United Press International.

In the study, which appears in the early online edition of the Proceedings of the National Academy of Sciences, Lowenhaupt's team studied the virus in the smallpox vaccine, which is called vaccinia and is closely related to the smallpox virus.

Vaccinia can be lethal in mice and is used as a model of human smallpox infection. It produces a protein called E3L that is essential to the virus' ability to cause death in mice. The action of E3L protein appears to depend on its ability to bind to Z-DNA, a segment of DNA that temporarily rotates in the opposite direction of normal DNA.

Lowenhaupt's team found by knocking out the region of the E3L protein to bind to Z-DNA, the virus was no longer lethal to mice.

Because the smallpox virus also has a E3L protein that is very similar to vaccinia's, the researchers concluded that developing a compound that blocks the Z-DNA binding region of E3L could help treat smallpox infection and block some of the side effects of the vaccine.

"If we can find a small molecule that will bind to or block that site ... it might very well prevent the virus from being able to replicate and thereby stop the infection from going any further," Lowenhaupt said.

They have already made some progress in test tube studies in the lab in identifying candidate molecules that appear to block the E3L protein, she said. "Once we feel confident of our candidates, we'll try it in mice," she said. But she noted a drug based on this premise would still be years away before it is ready for use in people.

Alexander Rich, principal investigator of the study and a professor of biophysics at MIT, told UPI that officials at the Centers for Disease Control and Prevention have been informed of the results and are eager to test compounds that block the E3L protein in their primate models of smallpox infection.

"People at CDC ... are very keen to test such small molecules to see if they are able to be used as therapy," Rich said. The CDC was unable to confirm this by press time.

In addition, several pharmaceutical companies "are very interested and I think this will get to be a big program," he said.

The National Institutes of Health sees promise in the concept and it is one of 10-15 targets for potential treatments for smallpox the agency is funding, Mark Challberg, a smallpox expert at the National Institute of Allergy and Infectious Diseases, told UPI.

However, not all researchers in the field were as enthusiastic about the possibility of the finding leading to a smallpox treatment.

Dr. Stewart Shuman of the Sloan-Kettering Institute's molecular biology program in New York said the E3L protein is "an unconventional target" for an anti-viral drug.

"Blocking virus replication directly would be a more sound strategy," Shuman told UPI, adding, "This study doesn't catapult this target up to the top of the list for me."

He noted, however, that the study is instrumental in understanding the role Z-DNA plays in the ability of viruses to cause illness in people.

In terms of developing treatments for vaccine side effects, Shuman said that might be unnecessary because "the issue of post-vaccine complications is going to be solved" when safer vaccines -- which are currently being developed -- are approved for use.

The new finding itself may lead to a safer vaccine, Challberg said. "The idea would be to remove that (Z-DNA-binding) domain from the standard vaccine and that might well make the new (vaccine) you create less pathogenic to humans," he said.

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(Reported by Steve Mitchell, UPI Medical Correspondent, in Washington)