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.
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Proceedings of the National Academy of Sciences