Posted on 02/01/2010 10:43:22 AM PST by decimon
Cell-culture and animal tests show antiviral could provide protection against HIV, Ebola, hepatitis C, herpes and more
GALVESTON, Texas — The development of antibiotics gave physicians seemingly miraculous weapons against infectious disease. Effective cures for terrible afflictions like pneumonia, syphilis and tuberculosis were suddenly at hand. Moreover, many of the drugs that made them possible were versatile enough to knock out a wide range of deadly bacterial threats.
Unfortunately, antibiotics have a fundamental limitation: They're useless against viruses, which cause most infectious diseases. Antiviral drugs have proven far more difficult to create, and almost all are specifically directed at a few particular pathogens — namely HIV, herpes viruses and influenza viruses. The two "broad-spectrum" antivirals in use, ribavirin and interferon-alpha, both cause debilitating side effects.
Now, researchers from the University of Texas Medical Branch at Galveston, UCLA, Harvard University, the U.S. Army Medical Research Institute of Infectious Diseases and Cornell University have teamed up to develop and test a broad-spectrum antiviral compound capable of stopping a wide range of highly dangerous viruses, including Ebola, HIV, hepatitis C virus, West Nile virus, Rift Valley fever virus and yellow fever virus, among others.
UCLA researchers led by Dr. Benhur Lee — corresponding author on a paper on the work appearing this week on the Proceedings of the National Academy of Science Web site — identified the compound (which they call LJ001), after screening a "library" of about 30,000 molecules to find a one that blocked the host cell entry of deadly Nipah virus. Subsequent experiments revealed that LJ001 blocked other viruses that, like Nipah, were surrounded by fatty capsules known as lipid envelopes. It had no effect on nonenveloped viruses.
"Once we started testing more and more, we realized that it was only targeting enveloped viruses," said Alexander Freiberg, director of UTMB's Robert E. Shope, M.D. Laboratory, the Biosafety Level 4 lab where much of the cell-culture work was done, as well as mouse studies with Ebola and Rift Valley fever viruses. "We followed up and determined that it was somehow changing the lipid envelope to prevent the fusion of the virus particle with the host cell."
Additional experiments indicated that while LJ001 also interacted with cell membranes, whose composition is nearly identical with that of virus envelopes, it caused them no ill effects. The reason, according to the researchers: Cells can rapidly repair their membranes, but viruses can't fix their envelopes.
"At antiviral concentrations, any damage it does to the cell's membrane can be repaired, while damage done to static viral envelopes, which have no inherent regenerative capacity, is permanent and irreversible," said Lee.
###
UTMB authors of the PNAS paper include graduate student Sara Woodson and adjunct associate professor Michael Holbrook, former director of the Shope BSL4 lab and principal investigator on the UTMB portion of the project. UCLA contributors are Mike Wolf, Tinghu Zhang, Zeynep Akyol-Ataman, Andrew Grock, Patrick Hong, Natalya Watson, Angela Fang, Hector Aguilar, Robert Damaoiseaux, John Miller, Steven Chantasirivisal, Vanessa Fontanes, Oscar Negrete, Paul Krogstad, Asim Dasgupta, Kym Faull and Michael Jung. Other authors are Jianrong Li and Sean Whelan of Harvard; Matteo Porotto and Anne Moscona of Cornell; and Anna Honko and Lisa Hensley of USAMRIID.
The National Institutes of Health, the UCLA Center for AIDS Research, the Burroughs Wellcome fund, the March of Dimes, the California Nanosystems Institute and the Warsaw Fellowship Endowment supported this research.
ABOUT UTMB: Established in 1891, Texas' first academic health center comprises four health sciences schools, three institutes for advanced study, a research enterprise that includes one of only two national laboratories dedicated to the safe study of infectious threats to human health, and a health system offering a full range of primary and specialized medical services throughout Galveston County and the Texas Gulf Coast region. UTMB is a component of the University of Texas System.
The University of Texas Medical Branch at Galveston Public Affairs Office 301 University Boulevard, Suite 3.102 Galveston, Texas 77555-0144 www.utmb.edu
Fat and static ping.
The author is not claiming that pneumonia and syphillis aren’t bacterial infections.
Reread it. The reference was to the usefulness of antibiotics.
The author was making an analogy to the success of antibiotics.
This is a huge story.
If it results in an effective treatment for tubby viral infections.
Looks pretty credible to me.
Pneumonia can be both viral or bacterial.
Excellent!
Thanks.
Now what did you think of the article?
A broad-spectrum antiviral targeting entry of enveloped viruses
We describe an antiviral small molecule, LJ001, effective against numerous enveloped viruses including Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically intercalated into viral membranes, irreversibly inactivated virions while leaving functionally intact envelope proteins, and inhibited viral entry at a step after virus binding but before virus–cell fusion. LJ001 pretreatment also prevented virus-induced mortality from Ebola and Rift Valley fever viruses. Structure–activity relationship analyses of LJ001, a rhodanine derivative, implicated both the polar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus–cell but not cell–cell fusion, and further studies with lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic window that exists between static viral membranes and biogenic cellular membranes with reparative capacity. In sum, our data reveal a class of broad-spectrum antivirals effective against enveloped viruses that target the viral lipid membrane and compromises its ability to mediate virus–cell fusion.
IMHO, this is big.
later.
Cheers!
Researchers find 'broad spectrum' antiviral that fights multitude of viruses
Compound could be used against HIV-1, Nipah, Ebola and other deadly viruses
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 Proceedings of the National Academy of Sciences, the researchers have identified an antiviral small molecule that is effective against numerous viruses, including HIV-1, influenza 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 hepatitis C 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 Rift Valley fever virus 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. The study is available in Proceedings of the National Academy of Sciences at http://www.pnas.org/content/early/2010/01/27/0909587107. Other authors are Mike C. Wolf, Tinghu Zhang, Zeynep Akyol-Ataman, Andrew Grock, Patrick W. Hong, Natalya F. Watson, Angela Q. Fang, Hector C. Aguilar, John P. Miller, Steven Chantasirivisal, Vanessa Fontanes, Oscar Negrete, Robert Damoiseaux, Paul Krogstad, Asim Dasgupta, Kym F. Faull and Michael E. Jung, all of UCLA; Alexander N. Freiberg, Sara E. Woodson and Michael R. Holbrook, of the University of Texas at Galveston; Jianrong Li and Sean P. Whelan, of Harvard University; Matteo Porotto and Anne Moscona, of Cornell University; and Anna N. Honko and Lisa E. Hensley, of the United States Army Medical Research Institute of Infectious Diseases. The National Institutes of Health, UCLA CFAR, the Burroughs Wellcome Fund, the March of Dimes, the California NanoSystems Institute, a UCLA Microbial Pathogenesis Training Grant, the Warsaw Fellowship Endowment, and a Rheumatology Training Grant funded this research. The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social science, public health, nursing, and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer. For more news, visit the UCLA Newsroom and follow us on Twitter.
http://www.eurekalert.org/pub_releases/2010-02/uoc--rf020110.php
Researchers find 'broad spectrum' antiviral that fights multitude of viruses
Compound could be used against HIV-1, Nipah, Ebola and other deadly viruses
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 Proceedings of the National Academy of Sciences, the researchers have identified an antiviral small molecule that is effective against numerous viruses, including HIV-1, influenza 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 hepatitis C 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 Rift Valley fever virus 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. The study is available in Proceedings of the National Academy of Sciences at http://www.pnas.org/content/early/2010/01/27/0909587107.
Other authors are Mike C. Wolf, Tinghu Zhang, Zeynep Akyol-Ataman, Andrew Grock, Patrick W. Hong, Natalya F. Watson, Angela Q. Fang, Hector C. Aguilar, John P. Miller, Steven Chantasirivisal, Vanessa Fontanes, Oscar Negrete, Robert Damoiseaux, Paul Krogstad, Asim Dasgupta, Kym F. Faull and Michael E. Jung, all of UCLA; Alexander N. Freiberg, Sara E. Woodson and Michael R. Holbrook, of the University of Texas at Galveston; Jianrong Li and Sean P. Whelan, of Harvard University; Matteo Porotto and Anne Moscona, of Cornell University; and Anna N. Honko and Lisa E. Hensley, of the United States Army Medical Research Institute of Infectious Diseases.
The National Institutes of Health, UCLA CFAR, the Burroughs Wellcome Fund, the March of Dimes, the California NanoSystems Institute, a UCLA Microbial Pathogenesis Training Grant, the Warsaw Fellowship Endowment, and a Rheumatology Training Grant funded this research.
The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social science, public health, nursing, and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer.
For more news, visit the UCLA Newsroom and follow us on Twitter.
http://www.eurekalert.org/pub_releases/2010-02/uoc--rf020110.php
UTMB-Galveston almost shut it’s doors after Hurricane Ike......glad they turned that decision around.
Ping... (Thanks, neverdem!)
I think it’s absolutely huge. I think it could even be bigger than the discovery of antibiotics.
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.