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MIT research may lead to smallpox drug

Poster created prior to 1979 promoting the importance of smallpox vaccination
Poster created prior to 1979 promoting the importance of smallpox vaccination
Image courtesy / Centers for Disease Control

CAMBRIDGE, Mass.--While the nation wrestles with the complications of vaccinating health professionals against smallpox, MIT researchers report this week in the online early edition of the Proceedings of the National Academy of Sciences (PNAS) that they have identified a potential new way to combat the disease.

In the vaccinia virus, a cousin of the lethal smallpox virus, the researchers found how one end of a specific protein called E3L within the virus is necessary for mice infected with the virus to sicken and die. Without the E3L protein, the virus can't kill.

A protein with an almost identical sequence is found in the related smallpox virus. The E3L protein is similar to a family of proteins that have been shown to be Z-DNA binding proteins.

In 1979, Alexander Rich, the William Thompson Sedgwick Professor of Biophysics at MIT, uncovered a new form of DNA dubbed Z-DNA that coils in the shape of a left-handed screw. He later found that this alternate version of the more common right-handed double helix exists briefly during transcription and is involved in editing genetic messages. Still on the quest to determine Z-DNA's biological role, he is now studying proteins that bind to it specifically.

Rich speculates that viruses take advantage of the vulnerability of DNA during the transcription process to insinuate themselves into the host's genetic material and block transcription.

When the researchers at MIT and Arizona State University substituted proteins for E3L that could not bind to Z-DNA or added mutations that lowered the segment's Z-DNA-binding ability, the virus lost some or all of its killing power.

"That's telling us that up to a point, we have a good correlation between binding to Z-DNA and the pathology," Rich said. In fact, the more strongly the protein bound to Z-DNA, the more lethal the virus it produced.

To come up with a therapy for smallpox, researchers would have to find a molecule that would bind to precisely the spot where E3L binds and prevent E3L from binding.

"The E3L of variola [the smallpox virus] is almost identical" to vaccinia E3L, Rich said. "I think the right small molecule will also bind E3L and prevent pathology for both viruses." Blocking E3L binding could offer treatment for smallpox infection and may also prevent unfavorable reactions to the smallpox vaccine.

"If we can prevent monkeys from getting smallpox, we have a therapy that takes away the incentive to use smallpox in a bioterrorist attack. If you knew someone was exposed, you could give it to the person or distribute it as a preventive measure," he said. A drug therapy could also be used for people who cannot be vaccinated, or that may be used to prevent unfavorable reactions to smallpox vaccinations.

In addition to Rich, authors include Bertram L. Jacobs, Maneesha Muralinath, Teresa Brandt and Kevin Hauns of Arizona State University; and Yang-Gyun Kim and Ky Lowenhaupt, research scientists in the MIT Department of Biology.

This work is funded by the National Institutes of Health and the Dana Foundation.

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