Researchers identify potential broad spectrum antiviral drugBMJ 2010; 340 doi: http://dx.doi.org/10.1136/bmj.c800 (Published 10 February 2010) Cite this as: BMJ 2010;340:c800
Researchers have identified a potential new antiviral agent that is effective against common flu, rare Ebola virus, and a host of viruses in between, including HIV.
The small molecule, named LJ001, targets lipids in enveloped viruses and prevents their entry into cells during the fusion process in which a virus enters a cell, say researchers in a paper published online in the Proceedings of the National Academy of Sciences of the United States of America (doi:10.1073/pnas.0909587107).
The research began with the screening of a library of 30 000 molecules for activity against the deadly Nipah virus by a team at the University of California, Los Angeles under a grant from the US National Institutes of Health’s biodefence research fund. It would later involve researchers at the University of Texas Medical Branch at Galveston, the US army, and elsewhere.
A series of tests in cell cultures led the study’s senior author, Benhur Lee, to conclude that LJ001 binds to lipids in the membranes of both the cell and the enveloped virus. The difference is that the cells have mechanisms to repair the damage done by the compound, while viruses do not.
“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,” said Dr Lee.
Further study found activity against more than 20 enveloped viruses, from the deadly rare Marburg virus to more common scourges such as the hepatitis C and West Nile viruses.
Serial passage of HIV-1 in a subneutralising concentration of LJ001 for four weeks (25-30 life cycles of the virus) saw no evidence of a decrease in sensitivity to the compound. It supports the view that perhaps the virus cannot generate resistance to drugs that have this mechanism of action.
The research team tweaked the molecular structure of the compound in various ways and saw how those rearrangements increased, decreased, or even neutralised its activity.
Heavy doses of LJ001 in mice yielded “no gross toxicity”; the most serious seemed to be slightly elevated serum cholesterol concentrations, Dr Lee wrote.
However, serum concentrations of the compound were suboptimal. Perhaps tinkering with the compound structure and drug formulation can increase bioavailability; otherwise, LJ001 has possible topical use as a microbicide against HIV or herpes or as an inhalant for use against respiratory viruses.
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, has “always held that a substantial amount [of biodefence funding] will be spent on the basic and clinical research aimed at a much broader scope of emerging and re-emerging infectious diseases that pose public health threats and not restricted to what we classically think of as bioterror agents.”
He called this study “a poster child of that concept,” in that compounds derived from it might have activity against the entire class of enveloped viruses.
“The potential implications of this study are very broad,” he said.
Cite this as: BMJ 2010;340:c800