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While it may seem slightly disconcerting, we often use medicines that we don’t fully understand how, or why they work.
At least, not on a molecular level.
And while that sort of knowledge may seem a bit esoteric to some (after all, if it works, who cares?), knowing how a drug works gives us insight in how to create new, more effective medicines.
Amantadine was one of the earliest antivirals (approved in 1966), developed in the wake of the 1957 Asian Flu pandemic. In 1969 it was also discovered to reduce the symptoms of Parkinson’s Disease and has since been used in the treatment of Multiple Sclerosis.
By 2008, however, the H3N2 seasonal flu had become 100% resistant to Amantadine, and the novel H1N1 of 2009 is resistant as well. Amantadine is still effective for seasonal H1N1, although that strain has rarely been seen since last summer.
Despite its long history of use, scientists have never quite understood how Amantadine binds to the flu virus and blocks replication. While growing resistance has greatly reduced Amantadine’s role in the treatment of influenza, this knowledge could lead to the creation of newer, more effective drugs.
Today, scientists at Iowa State University and the Ames Laboratory believe they’ve solved that mystery.
This from PhysOrg.com
Chemists discover how antiviral drugs bind to and block flu virus
February 3, 2010
Chemists from Iowa State University and the Ames Laboratory, left to right, Sarah Cady (who's holding a nuclear magnetic resonance probe), Mei Hong and Klaus Schmidt-Rohr are studying antiviral drugs and how they bind to flu viruses. Image: Bob Elbert/Iowa State University
Antiviral drugs block influenza A viruses from reproducing and spreading by attaching to a site within a proton channel necessary for the virus to infect healthy cells, according to a research project led by Iowa State University's Mei Hong and published in the Feb. 4 issue of the journal Nature.
Hong, Iowa State's John D. Corbett Professor of Chemistry and an associate scientist for the U.S. Department of Energy's Ames Laboratory, said the findings clarify previous, conflicting studies and should pave the way to development of new antiviral drugs against influenza viruses, including pandemic H1N1.
Two papers published by Nature in 2008 came to different conclusions about where the antiviral drug amantadine binds to a flu virus and stops it from infecting a healthy cell. A paper based on X-ray studies concluded the drug attached to the lumen of the proton channel, the area inside the channel, and stopped the virus by blocking the channel. Another paper based on solution nuclear magnetic resonance (NMR) technology concluded the drug attached to the surface of the virus protein near the proton channel and stopped the virus by indirectly changing the channel structure.
Hong's research concluded that when amantadine is present at the pharmacologically relevant amount of one molecule per channel, it attaches to the lumen inside the proton channel. But the paper also reports that when there are high concentrations of amantadine in the membrane, the drug will also attach to a second site on the surface of the virus protein near the channel.
Although this is a pay-per-view article, you can read the abstract in the journal Nature.
Nature 463, 689-692 (4 February 2010) | doi:10.1038/nature08722;
Received 31 August 2009; Accepted 27 November 2009
Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers
Sarah D. Cady, Klaus Schmidt-Rohr, Jun Wang, Cinque S. Soto, William F. DeGrado & Mei Hong
