Monday, August 15, 2011

The Indomitable Antiviral:

A paper has recently published in PLoS ONE detailing a new antiviral that has the potential to cure any viral infection that is caused by a virus that produces dsRNA. The new antiviral has been shown effective against 15 different viruses among them the author notes dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. All signs point to the virus being nontoxic.
What really caught my attention though is a statement in the MIT press release:

Karla Kirkegaard, professor of microbiology and immunology at Stanford University [said] “Viruses are pretty good at developing resistance to things we try against them, but in this case, it’s hard to think of a simple pathway to drug resistance.”

Why is it hard to image a pathway for resistance? The antiviral is a combination of two protein domains one from an interferon pathway and the other from an apoptosis pathway. The “PKA dsRNA binding motif” is the domain from the interferon pathway & the second domain is a procaspase for initiating apoptosis. Both of these domains do not become active until late in the immune response &  most viral defenses act early in the immune pathway so presumably viruses do not have inhibitors for the binding motifs or most procaspases.  

Viruses have been under more selective pressure to prevent the activation of PKA and procaspases then to inhibit them once they have been activated. This is due to the signaling cascades typical of cellular signaling. The sooner it acts in the cascade the fewer the inhibitors it must manufacture. Even if the viruses evolve an inhibitor for the  binding motif or procaspases, since the antiviral appears to be non-toxic it could be applied in dosages capable of overwhelming the inhibitors.

P.S.

While looking into this matter I found an interesting paper by some researchers who thought that they had come up with an antiviral that viruses could not evolve resistance to only to discover that they were wrong. They offer some insights into what went wrong and the characteristics they believe are required for an evolution proof cure.

J.A. Gibbons

References:  

Broad-Spectrum Antiviral Therapeutics. Todd H. Rider*, Christina E. Zook, Tara L. Boettcher, Scott T. Wick, Jennifer S. Pancoast, Benjamin D. Zusman. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0022572

Anne Trafton, MIT News Office. August 10, 2011. New drug could cure nearly any viral infection. http://web.mit.edu/newsoffice/2011/antiviral-0810.html


Viral Resistance Evolution Fully Escapes a Rationally Designed Lethal Inhibitor. Thomas E. Keller, Ian J. Molineux, Ian J. Molineux. Molecular Biology and Evolution. First published online: June 3, 2009 http://mbe.oxfordjournals.org/content/26/9/2041.full?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=Viral+drug+resistance&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

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