Monday, April 5, 2010

Finding a Medical "Silver Bullet"

From: <moderator@PORTSIDE.ORG

Finding a Medical "Silver Bullet" to Disable Many of the World's Deadliest

A series of promising compounds can cripple all enveloped viruses' ability
to invade cells as well as circumvent any resistance that hobbles
traditional antiviral drugs. But will they work outside the lab?

By Bob Roehr
Scientific American March 29, 2010

Benhur Lee may have discovered a medical silver bullet that can disable
pandemic HIV, exotic Ebola, the common flu and possibly every kind of
enveloped virus on the planet. An added bonus is that those viruses likely
are unable to develop resistance to the compound.

If this sounds too good to be true, you are not alone. Lee was skeptical
himself, and that is why it took four years of detailed work by his lab at
the University of California, Los Angeles, (U.C.L.A.), along with
collaborators spread across the country before the first paper was published
on the potentially revolutionary discovery, on February 16 in Proceedings of
the National Academy of Sciences.

Lee is an expert on the viral envelope, the dynamic outside surface of a
virus that latches onto a cell, then changes its shape to let the virus
enter and infect the cell. This work began as part of a biodefense grant
from the National Institutes of Health, screening a library of 30,000
compounds for activity against the envelope of Nipah virus, an emerging
infection first identified in 1999 in Malaysia.

Nipah is so deadly that work with the virus itself can only be done in
biosafety level 4 (BSL-4) labs where researchers wear tightly sealed hazmat
suits with internal oxygen supplies. The labs themselves are strongly
secured. There are only four in the U.S.

Lee got around that by creating a hybrid virus. He striped off the envelope
covering the relatively benign vesicular stomatitis virus (VSV) and added
the Nipah envelope to that core. This allowed him to screen the compounds in
his lab at the university using much lower BLS-2 safety standards, to see if
they inhibited viral entry into the cell.

"One compound (LJ001) looked really good, it had an IC50 of one micromolar
[meaning that it inhibited the pathogen at a low concentration], which for
an initial read is okay. Most importantly, it wasn't toxic" to cell
cultures, Lee explained.

Mike Wolf, a grad student in the lab, wanted to make sure the compound was
specific to Nipah, so he screened it against VSV. When the inhibition curves
came back identical, he originally was disappointed because the study's
funding was based on exploring potential therapeutics for Nipah.

Lee, however, encouraged him to be more persistent, and curious. After a
series of studies confirmed the activity and lack of toxicity, Lee sent
double-blinded samples of the compound and control to a colleague at the
BSL-4 lab at the University of Texas Medical Branch at Galveston who tested
it against Nipah, Ebola and other viruses. They were shocked when LJ001
inhibited viral entry to all of them.

So Lee pitted it against HIV, a pathogen he had worked with extensively-it
worked there, too. "That didn't make any sense at all to a virologist,
because retroviruses have nothing to do with these negative-strand RNA
viruses" like Nipah and Ebola, he says.

"We started going through a list of 20-plus viruses," and it inhibited entry
of all of them. "I had no idea of what was going on, I couldn't find
anything common about them." Finally, when he ran the compound against
adenovirus, it came back negative. Only then did he recognize the
commonality: LJ001 worked against lipid envelope viruses only. It took a few
years to rule out possibilities that the compound might be inhibiting the
binding or fusion processes by which such viruses enter cells.

Lee demonstrated that the compound binds to lipids in the envelope of both
the virus and the invaded cell. Eventually he came to realize that it causes
damage to both organisms. The difference is that the larger cell is equipped
to repair all sorts of regularly occurring insults. The more primitive
virus, however, carries no repair mechanisms; a new virion (complete virus)
acquires lipids for its envelope by literally ripping them off of the
cellular membrane as it buds off from the infected cell. Once the viral
lipids were disabled by LJ001 they stayed that way.

Current antiviral drugs target encoded proteins essential to the viral life
cycle, and which vary so much among virus types that a specifically tailored
drug seldom is effective against more than one of them. Furthermore, active
processes allow viruses to inevitably develop resistance to such compounds.
To compensate for this shortcoming, combination therapy attempts to hit a
virus at so many places simultaneously that it cannot develop resistance to
them all.

But viruses do not have genetic control of their lipids like they do with
proteins. So, Lee is optimistic about the potential for resistance to drugs
like LJ001. He says, "I can't imagine how the virus can develop resistance
to it."

When U.C.L.A. lawyers searched the patent database, they found that a
company already had filed a patent on LJ001 claiming antiviral activity but
describing little else. Lee is not concerned; his colleague Michael Jung, a
medicinal chemist at U.C.L.A., had tinkered with the original compound and
found a series of variations that are 100-fold more potent. The university
is filing claim to those.

Lee says it is important to demonstrate in vivo efficacy of these compounds.
He is working to try to overcome a few barriers they have identified, and he
readily concedes that it will take teams of experts with specialized
knowledge to bring a product to market. His primary focus is on basic
research, and he already is thinking about those next challenges.

Warner Greene, director of the Gladstone Institute of Virology and
Immunology at the University of California, San Francisco, congratulated Lee
and his collaborators on "a fascinating piece of work on an unexpected
finding." But, he cautions, "from a therapeutic point of view it is a very,
very early finding."

"The breadth of antiviral activity is fascinating but I fear that with the
underlying mechanism of membrane disruption, there might be a lot more
toxicity than is currently appreciated. Primary cells often are much more
sensitive than laboratory-adapted cells," Greene says.

He adds: "With this type of drug you are always going to be operating in a
window of whether or not the cell can catch up and keep the cell alive while
the drug is still being effective against the virus. It will be a race."
That is the same principle behind many current therapies for cancer.

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