7:20am

Sun July 1, 2012
Science

The Search For A Drug To Treat West Nile And Its Viral Cousins

With pools of mosquitoes confirmed to be carrying West Nile Virus across Colorado, West Nile season is officially here. If you get infected, though, don’t expect to run to the pharmacy. A pair of local researchers is trying to change that.

“Fresh cells served daily. Viruses dine free.” That’s what is written above one of the workspaces in Brian Geiss’s lab at Colorado State University in Fort Collins.

Lunch may be on the house now, but Geiss is looking for a way to end the complimentary meals. A compound he’s found is still in the early stages of drug discovery, but it’s able to limit the amount of virus growing in cells—a promising first step.

Geiss’s search for a drug began over six years ago, after West Nile Virus, a type of flavivirus, was at its peak in the United States. As a virologist, Geiss had taken notice.

“I started working on the flaviviruses mainly because of West Nile. But as I learned more about them, I really started to learn what worldwide problems they are.”

Geiss says there are about 35 different flaviviruses that can be passed to humans through mosquito bites, and two-thirds of the world’s population is at risk for at least one of them. The most notorious is Dengue virus, which infects over 50 million people per year, and kills about 22,000.

Despite the ubiquity of these viruses, there aren’t any drugs to treat them. But Geiss knew someone who might be able to help.

“A friend of mine from graduate school, Susan Keenan, and I were having dinner over at her and her husband’s house, and we started talking about science,” says Geiss.

Keenan had expertise in computational biology and chemistry. “It was over a glass of wine that we decided that we should collaborate,” says Keenan, a biology professor at the University of Northern Colorado.

Their idea was to try and design a drug that could take down not just Dengue, or West Nile, but as many of the flaviviruses all at once: No free lunches for anyone.

Normally, flaviviruses enter the body and start making copies of their RNA genomes so that they can be packaged up and sent out to infect other cells. But this only happens if a particular viral protein called a capping enzyme helps. Take away this enzyme, and viral proteins can’t be made.

“If you don’t get translation of those viral proteins,” says Geiss, “the virus can’t replicate its genome and you basically abort replication.”

Because most flaviviruses have similar capping enzymes, if one like West Nile can be stopped, then others can be stopped, too.

After screening nearly 300,000 existing compounds, Geiss and Keenan found five core structures that could block the capping enzyme to some extent. That meant it was time to go shopping—for more drugs.

“So we took the basic compounds from our screen and started ordering additional compounds that had little changes here or there,” says Geiss. “It’s like going to Amazon,” adds Keenan. Keenan proceeded to map which parts of the drug were most helpful, understanding and optimizing the drug candidate.

Geiss then added the best drug to hamster cells infected with Kunjin virus, a type of West Nile. After two days, the amount of virus was a thousand times lower than the untreated cells.

“Whenever you have an experiment or a hypothesis that really starts coming to fruition, it’s incredibly exciting,” says Keenan. “When we found out it worked against live virus, that was even more exciting.”

There is still a lot of work left, however, before pharmacies stock their shelves with the new antivirals.

“We are actively looking at human cell types, because we’re not that concerned with protecting hamsters from dengue,” says Geiss.

They also want to increase the activity of the drug so the dose can be lowered, and see if it really does work against a large number of other viruses.

But Geiss is optimistic.

“It looks like this particular drug might be able to get us down that road because we’ve seen it has efficacy against Dengue virus, against Yellow Fever virus, and against West Nile virus.”

Geiss estimates the drug won’t be ready for another 10 to 15 years, mostly because it would need to undergo rigorous clinical testing.  And even if they’re successful with this drug, more will need to be in the pipeline.

“Viruses replicate very, very quickly, and in doing so they can mutate very, very quickly,” says Keenan.

A high level of mutation means the viruses can evolve ways to get around the drug, and become resistant. For this reason, Keenan says she has three or four other drug families that are good candidates, and hopes to test them over the next six months.

So while there may never be an absolute end to the era of free meals, Geiss and Keenan hope to at least take a big bite out of viral mooching.

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