19 March 2002 13:09 EST

by Apoorva Mandavilli, BioMedNet News

Karl Hostetler

A new oral drug, designed to exploit the mechanism for absorption of dietary lipids, can protect against the smallpox virus, researchers will announce tomorrow at the International Conference on Antiviral Research in Prague.

The new drug is derived from cidofovir, an intravenous drug recently shown to be active against the poxvirus, and used to treat retinal infections caused by cytomegalovirus.

Achieving an oral drug against smallpox is critical, because only trained personnel can provide an intravenous medication. "With an intravenous drug, if you ever needed to use it for an outbreak, it would be very hard to use it widely," said lead investigator Karl Hostetler in a telephone interview from Prague. Hostetler is director of endocrinology and metabolism at the Veterans Affairs San Diego Healthcare System and professor of medicine at the University of California in San Diego.

The oral drug, hexadecyloxypropyl-cidofovir (HDP-CDV), is 100 times more potent than cidofovir in cowpox-infected mice, the researchers found. It is also effective against a variety of pox viruses in vitro, in as few as 5 daily doses. Before use in humans, the drug must be cleared for safety and tested in clinical trials.

The US government has recently funded efforts to create new stockpiles of smallpox vaccines, limited for use after a bioterrorist attack. In 1999, the US National Institutes of Health and the military also approached Hostetler and his colleagues to speed up the development of antivirals against smallpox.

None of that research would be possible without access to smallpox stocks, which are earmarked for destruction in December 2002, says Hostetler, calling the stocks a "national treasure."

Relying solely on vaccines to protect against a bioterrorist attack with smallpox is dangerous, Hostetler adds. "It's widely known in the scientific community that there are simple strategies to avoid vaccination entirely by altering the virus," he told BioMedNet News. "[An antiviral] drug is necessary."

In a preliminary experiment with a mouse version of the pox virus last year, scientists in Australia found it is possible to render the smallpox vaccine useless. But the experiment was in mice, points out Catherine Laughlin, chief of virology at the US National Institute of Allergy and Infectious Diseases. "It's not clear that would happen in humans," she said, and the manipulations to inactivate the vaccine were "not trivial."

"That doesn't mean we won't need the drug for other reasons," she said. In some cases, the vaccine is known to have serious side effects including secondary infections, encephalitis, and even death. It is also not safe for use in people with AIDS, cancer and, oddly enough, eczema.

Laughlin seconds Hostetler's objections to destroying the smallpox stocks. "The government's position, which I agree with, is that the stock should not be destroyed until we have drugs available that would work by at least two different mechanisms," she said. Ideally, the government should also acquire a safer vaccine and better diagnostics, she added.

In collaboration with researchers at the USAMRIID in Fort Detrick, Maryland, Hostetler designed the drug to mimic a naturally occurring dietary lipid, lyso-phosphatidylcholine. Based on his knowledge of esoteric lipid biochemistry, he replaced the choline phosphate with cidofovir and manipulated the compound to make it more stable.

Like dietary lipids, the compound is absorbed across the apical membrane of enterocytes (cells of the small intestine), transported through the cytoplasm to the basolateral surface of the cells and from there, enters the bloodstream. "We don't know how exactly it works but people don't really know how lyso-PC works either," Hostetler admitted.

Because blood lacks enzymes to cleave HPD-CDV, the compound passes through largely intact, until cellular enzymes cleave it to release cifodovir. Once activated, cifodvir blocks the viral DNA polymerase and inhibits viral replication.

Just 5 daily oral doses of HDP-CDV given to cowpox-infected mice prevented death from disease, the researchers found. Virus titers in the lung of infected animals were reduced to nearly undetectable levels.

Using the same approach, the researchers are now developing the herpes drug acyclovir for use against hepaptitis B, and the cytomegalovirus drug foscarnet to treat AIDS. "We think this strategy has some general applications beyond [smallpox]," Hostetler said.

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