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Vanquishing a Virus: New drugs attack herpes infections
John Travis

Best known for intermittently producing embarrassing sores on the mouth and genitals, herpes simplex virus (HSV) is more dangerous than most people realize. The virus can blind and even kill people with weak immune systems, such as newborns, elderly people, and AIDS patients.

By targeting one of the virus' enzymes, two pharmaceutical companies have now independently identified a new class of drugs that stop HSV from replicating. Scientists rate the compounds as the most promising antiherpes agents developed in 3 decades. Surprisingly, however, there are no current plans to test the experimental drugs in people.

First developed in the 1970s, the compound acyclovir remains the standard drug for treating various forms of HSV. When acyclovir gets into an infected cell, an HSV enzyme activates the drug, leading to the inhibition of a protein the virus uses to copy its own DNA. However, a treated infection may recur, and some strains of the virus are resistant to acyclovir.

Seeking new drug opportunities, researchers have looked at other proteins that the virus relies on to replicate its DNA. More than a decade ago, while at Stanford University, James J. Crute discovered a complex of three HSV proteins that combine into an enzyme called helicase-primase. The virus uses this enzyme to unravel DNA's double helix structure and perform other duties required for replication.

"It was immediately recognized as a really great target for drug discovery," recalls Crute, now at Aurora Biosciences in San Diego.

While working at Boehringer Ingelheim Pharmaceutical in Ridgefield, Conn., Crute and his colleagues developed an assay for screening thousands of compounds for ones that inhibit the helicase activity of the viral enzyme. They identified several compounds that hamper the enzyme's ability to creep along the DNA strand and perform its duties.

Crute's team reports in the April Nature Medicine that these inhibitors block HSV replication in infected cells and also help rodents survive HSV infections. In mice whose genitals had been infected with HSV, one inhibitor slashed the death rate from 60 percent to 10 percent.

Moreover, the new compounds are effective even when given to the mice up to 65 hours after an initial infection. In contrast, for acyclovir to work, it must be taken within hours after the first symptoms appear.

Gerald Kleymann and his colleagues at Bayer AG in Wuppertal, Germany, also have identified inhibitors of HSV replication. After screening more than 400,000 compounds, they realized that the most effective ones were interfering with helicase-primase.

"It appears that we hit the Achilles' heel of the virus," says Kleymann.

Like the Boehringer Ingelheim team, the Bayer group found the compounds to be effective in rodents infected with HSV. In the April Nature Medicine, the Bayer group even reports that its compounds reduce the number of sequelae—the subsequent outbreaks of sores after an initial infection.

"The unsolved problem of herpes infections, namely the sequelae, may become curable," says Kleymann.

Both research groups conclude that helicase-primase inhibitors are more potent than acyclovir and its derivatives.

"People have been looking for years, and nobody had come up with anything that matches acyclovir," notes virologist Priscilla A. Schaffer of Harvard Medical School in Boston. "These compounds are tremendously exciting."

At the moment, though, neither Bayer nor Boehringer Ingelheim plans to launch tests of helicase-primase inhibitors in people. "It's unfortunate because these compounds do look interesting, but companies have to make choices about what they are going to put their money and resources behind," says Paul Anderson, a vice president at Boehringer Ingelheim.

"The fundamental issue is that no pharmaceutical company wants to go head-to-head with acyclovir [and its derivatives]," says virologist Richard Whitley of the University of Alabama at Birmingham. "They do not see it as profitable."

Both pharmaceutical firms say they hope to find other companies willing to finance further testing of their compounds.

"It's kind of depressing," notes Schaffer. "We'd all love to see [a helicase-primase inhibitor] go into the clinic. One of these days, I dare say, it will."




References:

Crumpacker, C.S., and P.A. Schaffer. 2002. New anti-HSV therapeutics target the helicase-primase complex. Nature Medicine 8(April):327-328.

Crute, J.J., et al. 2002. Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nature Medicine 8(April):386-391. Abstract available at http://dx.doi.org/10.1038/nm0402-386.

Kleymann, G., et al. 2002. New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nature Medicine 8(April):392-398. Abstract available at http://dx.doi.org/10.1038/nm0402-392.

Sources:

James J. Crute
Aurora Biosciences
11010 Torreyana Road
San Diego, CA 92121
 

 
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