Emerging subtypes of influenza A virus hold the potential to initiate a world-wide epidemic in the next few years, according to World Health Organization officials. However, almost all type A influenza viral strains have become resistant to amantadine and rimantadine, two drugs that make up one of only two classes used to treat the flu. Researchers at the University of Pennsylvania School of Medicine have now provided a new strategy for designing drugs that target the resistant viral strains by solving the three-dimensional structure of a viral protein called the M2 proton channel. This protein is the molecular receptor for these drugs. This study is published in the Jan. 31 issue of Nature.
The M2 protein is located in the viral envelope, forming a long, narrow channel that allows the flow of protons into the viral interior, an essential step for infection. Amantadine sits in this channel and blocks the flow of protons, thus halting infection. In non-resistant viruses, amantadine acts like a cork lodged deep in the channel.
“We know that resistance to amantadine is caused by a mutation in the virus M2 protein, but we did not know how this mutation caused resistance,” explains senior author William F. DeGrado, PhD, Professor of Biochemistry and Biophysics. “Now we do – the mutation changes the shape of the channel so amantadine can no longer do its job.”
The structure revealed that there is a pocket in the channel next to the location where amantadine fits that is conserved in all influenza A viruses. This newly discovered space could be the target for new drugs. “Inhibitors that target this cavity adjacent to two highly conserved amino acids in M2 might reclaim the M2-blocking class of drugs so that ongoing endemic outbreaks and future pandemics of this deadly virus might be prevented and treated,” says DeGrado.
Release date: January 30, 2008
Source: University of Pennsylvania School of Medicine
Filed Under: Drug Discovery