New hope against flu

Researchers gain better understanding of drug-resistant influenza strains.

University of Pennsylvania School of Medicine researchers have identified a new technique to combat the resistant type A influenza by constructing a 3D structure of the viral protein called the M2 proton channel – the molecular receptor for flu fighting drugs.
 
The M2 protein – located in the viral envelope – has been crystallised so that its structure could be examined under different conditions using a technique called x-ray crystallography. Penn researchers carried out this study to better understand how the M2 protein in the viral envelope forms the long, narrow channel that allows the flow of protons into the viral interior, an essential step for infection.
 
The technique – called x-ray crystallography - allowed the researchers to bombard the pure protein crystal with x-rays so that the position of each atom in relation to its neighbouring atoms in the crystal would show up as an array of black spots. From the pattern of thousands of spots, the structure of the protein could be graphically visualised using computer imaging technology.

Emerging influenza A viruses

According to the World Health Organisation, emerging subtypes of influenza A virus hold the potential to initiate a world-wide epidemic in the next few years. Furthermore, A type viral strains have become resistant to the current treatment of drugs amantadine and rimantadine.
 
The researchers have observed that although amantadine is designed to block viral infection in non-resistant viruses, in resistant viruses a mutation occurs that has remained a mystery to scientists until now.
 
"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," explained 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 also 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," said DeGrado.
 
Next, the researchers want to design new compounds that plug the M2 channel by fitting into the newly discovered larger cavity.

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