Compound found that targets wide range of viruses

Feb 01, 2010 By Enrique Rivero

(PhysOrg.com) -- The compound was found to be effective against viruses that cause some of the world's deadliest diseases, such as AIDS, Ebola and Rift Valley fever.

Viruses are insidious creatures. They differ from each other in many ways, and they can mutate — at times seemingly at will, as with HIV — to resist a host of weapons fired at them. Complicating matters further is that new viruses are constantly emerging.

One potential weapon is a small-molecule "broad spectrum" antiviral that will fight a host of viruses by attacking them through some feature common to an entire class of viruses. For example, there are two categories of viruses: lipid-enveloped and non-enveloped. Enveloped viruses are surrounded by a membrane that in effect serves as a mechanism through which a virus inserts its genome into a host cell, infecting it. Is there something out there that might disrupt that action in as many viruses as possible — and not produce unwanted side effects?

A group of researchers led by a team from UCLA and including others from the University of Texas at Galveston, Harvard University, Cornell University and the United States Army Medical Research Institute of Infectious Diseases may have found just such a compound.

In a proof-of-principle study published online in , the researchers have identified an antiviral small molecule that is effective against numerous viruses, including HIV-1, A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses and flaviviruses. These viruses cause some of the world's deadliest diseases, such as AIDS, Nipah virus encephalitis, Ebola, hemorrhagic fever and Rift Valley fever.

Even better, the compound — a rhodanine derivative that the researchers have dubbed LJ001 — could be effective against new, yet-to-be discovered enveloped viruses.

"Since the government has changed its priorities to support development of broad spectrum therapeutics, more and more groups have been screening compound libraries for antivirals that are active against multiple viruses in a specific class," said Dr. Benhur Lee, associate professor of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA and the primary investigator of the four-year study.

U.S. Food and Drug Administration-approved broad spectrum antivirals do exist but are rare, for various reasons. Ribavirin, for instance, affects both the virus proteins and the host cell and is effective on only a limited number of viruses, such as respiratory syncytial virus and Lassa fever virus. And α-interferon, which is used against the virus, produces unwanted side effects and is too expensive for widespread use.

But the putative mechanism for LJ001 is surprising, according to Lee, who is also a member of the UCLA AIDS Institute.

"We provide evidence that the small molecule binds to both cellular and viral membranes, but its preferential ability to inactivate viral membranes comes from its ability to exploit the biogenic reparative ability of metabolically active cells versus static viral membranes," he said. "That is, at antiviral concentrations, any damage it does to the cell's membrane can be repaired, while damage done to static viral membranes, which have no inherent regenerative capacity, is permanent and irreversible."

Lee and his collaborators developed their concept of LJ001 as interfering only with enveloped viruses after testing 23 pathogens in cell culture. Studies of nine of those agents — including Ebola virus, Nipah virus and Rift Valley fever virus — required high- or maximum-containment facilities and were carried out in the biosafety level 3 and 4 laboratories of the University of Texas Medical Branch at Galveston (UTMB) and USAMRIID.

"Once we started testing more and more, we figured out that it was only targeting the enveloped viruses," said Alexander N. Freiberg, director of UTMB's Robert E. Shope, M.D., Laboratory.

The Shope BSL4 lab was also used for mouse experiments with Ebola and that further confirmed the protective value of LJ001.

While the exact mechanism of viral membrane inactivation is unknown, the researchers are pursuing some promising leads that could answer that question.

Additionally, the drug does not appear to be toxic in vitro or in animals when used at effective antiviral concentrations.

UCLA has filed for a patent on the use of the compound.

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User comments : 6

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Parsec
3 / 5 (2) Feb 01, 2010
I suspect that clinical testing for toxicity of this compound will reveal at least a sub-population that have serious or fatal side effects. I am praying with all my heart however that I am totally and absolutely wrong.
mertzj
Feb 01, 2010
This comment has been removed by a moderator.
fixer
1 / 5 (1) Feb 01, 2010
It's really well written, but it appears to be laying the foundation for a cure to virusses that haven't been invented yet.
I am always suspicious of reports that "appear to be" something and which are tested on mouse models, the immune systems have too many differences.
I think merti is correct, wait and see how the human trials go.
Moshe
1 / 5 (1) Feb 02, 2010
This may be then next great thing, a minor advance or disappear completely. Time and research will tell... But fixer - I think "appears to be" and such expressions in preliminary work is not used often enough. People say "will be" way too quickly - I think not overselling the story is positive.
tw60407
1 / 5 (1) Feb 02, 2010
I'm thinking either really bad side effects or mutants... ;-) 3/4 of our genome is made up of remnants of viral segments - does this article frighten anyone else? Also inspires... but count me out on the initial trials!
Skeptic_Heretic
1 / 5 (1) Feb 02, 2010
I am always suspicious of reports that "appear to be" something and which are tested on mouse models, the immune systems have too many differences.
We share about 80% of our immune system function with mice. We're both descended from primitive voles. It's apt to start testing there and then progress to more and more human like animals. Allows us to stop and recognize potential side effects without human capital expenditures.
jonnyboy
1 / 5 (1) Feb 02, 2010
You all act like millions of people are not dying at this very moment from all of these viruses and ensuing complications. We have a desperately in need population that is more than willing to submit themselves to human trials rather than die next week or next month.