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An antiviral for enveloped viruses

Posted Feb 18 2010 12:00am

LJ001Broad spectrum antibiotics are available that act against a wide range of bacteria, including both gram-positive and gram-negative species. In contrast, our antiviral arsenal is exceedingly specific. Nearly all the known antivirals block infection with one or two different viruses. The discovery of a compound that blocks infection with many different enveloped viruses may change the landscape of antiviral therapy.

A small molecule has been discovered that inhibits infection by a wide range of viruses with membranes, the so-called enveloped viruses. The compound, called LJ001, is a derivative of aryl methylene rhodanine. It was discovered in a search for compounds that block the entry of Nipah virus into cells. LJ001 was then found to block infection of cells by a wide variety of enveloped viruses, including filoviruses (Ebola, Marburg); influenza A virus; arenaviruses (Junin), bunyaviruses (Rift Valley fever virus, LaCrosse virus); flaviviruses (Omsk hemorrhagic fever virus, Russian spring-summer encephalitis virus, yellow fever virus, hepatitis C virus, West Nile virus); paramyxoviruses (Nipah virus, parainfluenza virus, Newcastle disease virus); retroviruses (HIV-1, murine leukemia virus); rhabdoviruses (vesicular stomatitis virus); and poxviruses (cowpox virus, vaccinia virus). The compound had no effect on viruses without an membrane, such as adenovirus, coxsackievirus, and reovirus.

To determine which step of viral infection is blocked, LJ001 was added at different times during infection. Inhibition of infection was observed when LJ001 and virus were incubated before being added to the cell. However, if the virus was allowed to enter the cell, addition of the compound had no effect on the production of infectious virus. Inclusion of LJ001 into the culture medium did prevent virus spread to neighboring cells.

LJ001 inhibits such a wide spectrum of viruses because it targets a feature common to all of them: the viral envelope (see image of influenza virus for an example). The compound blocks virus infection by inserting into the viral membrane and inhibiting entry into the cell. It does not block virus attachment to cells, but impairs fusion of the viral and cell membranes, a step essential for entry of the viral genome into cells. However, LJ001 is not toxic to cells, and does not inhibit the fusion of neighboring cells caused by some viral infections.

How might LJ001 impair viral but not cellular membranes? One explanation is that the compound damages both viral and cell membranes. The latter can be repaired and consequently escape the toxic effects of the drug. In contrast, viral membranes are static, and once damaged by LJ001 they can no longer function properly during virus entry into cells.

Whether LJ001 and derivatives will be useful for treating virus infections in animals awaits the results of testing in animal models and then in humans. Meanwhile, an interesting question is whether viral mutants resistant to LJ001 and its derivatives will emerge. Just because the drug targets a component derived from the host cell does not mean that resistance will not emerge. The drug brefeldin A, an inhibitor of poliovirus, blocks a cellular enzyme, yet viral mutants resistant to the drug have been identified. One possibility for the mechanism of resistance could be amino acid changes in viral glycoproteins that protect the viral membrane from damage caused by LJ001.

Perhaps it’s not a matter of whether mutants resistant to LJ001 will emerge, but when they will be identified.

Wolf, M., Freiberg, A., Zhang, T., Akyol-Ataman, Z., Grock, A., Hong, P., Li, J., Watson, N., Fang, A., Aguilar, H., Porotto, M., Honko, A., Damoiseaux, R., Miller, J., Woodson, S., Chantasirivisal, S., Fontanes, V., Negrete, O., Krogstad, P., Dasgupta, A., Moscona, A., Hensley, L., Whelan, S., Faull, K., Holbrook, M., Jung, M., & Lee, B. (2010). A broad-spectrum antiviral targeting entry of enveloped viruses Proceedings of the National Academy of Sciences, 107 (7), 3157-3162 DOI: 10.1073/pnas.0909587107

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