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Enzyme studies at Brookhaven Lab may lead to new antiviral agents

UPTON, NY -- Three new enzyme studies at the U.S. Department of Energy's Brookhaven National Laboratory have yielded a new strategy for blocking infection by human adenovirus. The findings, reported in the October, November, and December issues of the journal Biochemistry, have already been used to design novel antiviral drugs.

Adenoviruses cause a number of acute infections, including respiratory and gastrointestinal infections, and also conjunctivitis. In patients with compromised immune systems, such as those infected with human immunodeficiency virus (HIV), an opportunistic adenovirus infection is frequently deadly. "Our new antiviral drugs are expected not only to inhibit adenovirus, but might also be effective against other organisms that use the same enzyme -- including Chlamydia, one of the most prevalent sexually transmitted diseases, and Yersinia pestis, the organism that causes the black plague," said Walter Mangel, the lead scientist on the studies.

During infection, these viruses make an enzyme called a protease, which cleaves or degrades other proteins. The protease is used by the virus to complete the maturation of newly synthesized virus particles. To explain this process, Mangel uses the example of building a cathedral around internal scaffolding. Once the cathedral is in place, the last step is to remove the scaffolding. "Similarly," says Mangel, "adenovirus particles are built with scaffolding protein inside. Once the virus particle is formed, the protease becomes activated and cleaves the scaffolding to render the virus particle infectious."

The three recent Brookhaven studies reveal that the protease is initially synthesized in an inactive form. The inactive enzyme binds to the viral DNA to become partially activated.

"Such activation of a protease by DNA has never been seen before," Mangel said.

The partially activated enzyme then cleaves out a cofactor (a protein fragment), which binds to the protease to
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Contact: Karen McNulty Walsh
kmcnulty@bnl.gov
631-344-8350
DOE/Brookhaven National Laboratory
4-Dec-2001


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