Broad 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
Other than development of resistance against the drug there are afew more questions that need to be addressed. (1) The half-life appears to be too short -~4h (2) Since the drug depends of biogenerative repair of cell membranes – are there cells in some tissues that do not have as rapid membrane repair? (3) can the drug cross the blood-brain barrier and if so what is its effect(s)?
These are important questions. Presumably the chemists will address
the half life and uptake/pharmacology issues by producing derivatives.
The tissue-specific issue is a good one.
A basic point – mammalian cells don't need to be able to merge with those of other cells, quite the opposite. It may just mildly improve cell membrane stability, with no toxicity whatsoever.
It is interesting that LJ001 inhibits such a variety of enveloped viruses. Because of its non-specific inhibitory effect, LJ001 seems to target the viral envelop membrane rather than glycoproteins. Might this suggest that it should be more tolerant for mutations than the other anti-viral drugs? And is this the first compound identified to target the virus envelop membrane to block the fusion? As far as I know, it is obliviously different from HIV fusion inhibitors, Maraviroc and Enfuvirtide, which targets CCR5 co-receptor and member glycoprotein respectively.
Pingback: uberVU - social comments
when it works against so many enveloped, entirely different viruses (and fails on none ?)
then I'd assume there is no potential for resistance
I would not make the assumption that resistance cannot emerge just
because many viruses are inhibited. Ribavirin inhibits a number of
different viruses, yet resistance to that drug is observed. Each virus
could evolve to LJ001 resistance in different ways.
Yes, but the drug could have other effects in an animal that are not
evident in cell culture. Larger scale animal toxicity studies will
address this question.
As a medical student we have been taught that when both the fluoroquinolone and oxazolidinone antibiotics were first developed it was believed that it would be impossible for bacterial resistance to develop due to their incredibly novel mechanisms of action and entirely synthetic nature. Resistance has subsequently seen to both of these. Nature is a cunning foe and has been fighting this fight for billions of years. I have come to the conclusion that resistance will always develop as, so far, it always has.
I've been thinking about resistance too and in my eyes the solution to this problem will come up in the distant future through a change of view. Don't eliminate certain viruses or bacteria but find out what is part of a healthy cell and human body and eliminate the rest no matter what it is. Impossible right now but maybe possible in the future, like growing organs, resetting immune systems and scanning cells for things that don't belong there.
I work with a natural compound that also has a broad spectrum of action. It has a cellular target: it interferes with the glycoprotein traficking without cytotoxicity [1] . Just because the drug targets a component derived from the host cell , it has another important dvantage: it has immunomodulatory properties, that would improve the immunopathology associated with the viral infection [2,3].
[1] 1-Cinnamoyl-3,11-dihydroxymeliacarpin delays glycoprotein transport restraining virus multiplication without cytotoxicity. Bueno CA, Alché LE, Barquero AA. Biochem Biophys Res Commun. 2010 Feb 26;393(1):32-37. Epub 2010 Jan 25.
[2] A natural tetranortriterpenoid with immunomodulating properties as a potential anti-HSV agent. Bueno CA, Barquero AA, Di Cónsoli H, Maier MS, Alché LE. Virus Res. 2009 Apr;141(1):47-54. Epub 2009 Jan 20.
[3] Therapeutic action of meliacine, a plant-derived antiviral, on HSV-induced ocular disease in mice. Pifarré MP, Berra A, Coto CE, Alché LE. Exp Eye Res. 2002 Sep;75(3):327-34.
There are known the receptors of human cells which the ebola virus joins ? Is the well-read one who has studied the interaction of the protein VP35 but not understand the function, also it was speaking about the interaction with a RNA that tape-worm effect on the evasion of the immune response.
Just where did this compound originate? From human cells? It looks like it came from lipids.
LJ001 is a synthetic compound, made by chemists. It was part of a
large chemical library that was used to screen for inhibitors of Nipah
virus entry.
LJ001 is a “synthetic” compound produced by chemists. Where and who produced it and for what reason? And is it really synthetic/man-made and can be created in a lab via chemistry not through biological cells? Where did this library of compounds originate?
Just where did this compound originate? From human cells? It looks like it came from lipids.
LJ001 is a synthetic compound, made by chemists. It was part of a
large chemical library that was used to screen for inhibitors of Nipah
virus entry.
LJ001 is a “synthetic” compound produced by chemists. Where and who produced it and for what reason? And is it really synthetic/man-made and can be created in a lab via chemistry not through biological cells? Where did this library of compounds originate?
Why aren't these molecules cleaved by proteases ??
They are not proteins, hence not cleaved by proteinases.
 Welcome. I am student microbiology and molecular biology from Poland and I would like to know something more about this method.
I was wondering if this compound would work against the flavivirus that causes Murray Valley Encephalitis- just heard about a policeman who was completely paralysed & lost his speech.
nao se falam mais na droga DRACO que mata todos os virus. alguem tem noticias?
DRACO – A DROGA QUE MATA TODOS OS VIRUS. alguem tem novidades por ai?