ANU researchers reveal new influenza target

Infuenza is a tough virus to crack. Today we’re fortunate to have two neuraminidase inhibitors - oseltamivir (Tamiflu) and zanamivir (Relenza) - that are very effective at stunting the spread of influenza.

In the 1960s there was also another class of anti-virals that used to stop influenza in its tracks: adamantanes, although the influenza virus has now developed a resistance against these drugs making them largely ineffectual today.

However, the mechanisms by which adamantanes flummoxed influenza are still of interest to scientists, and controversy has reigned over the last couple of years as to precisely what those mechanisms are.

It was known that adamantanes targeted and inhibited a proton-selective ion channel, M2, but it was uncertain exactly what the binding sites were for the drug.

Now researchers from The Australian National University have settled the controversy and revealed that adamantanes bound to two sites on M2, and found that only one of these was the primary site for its pharmacological action.

This discovery suggests that M2 could still be a viable target for anti-influenza drugs, opening up the possibility of developing new anti-virals to complement oseltamivir and zanamivir.

The researchers, Dr Marco Casarotto and PhD student, Mr Matthew Rosenberg, of the John Curtin School of Medical Research at ANU, conducted a series of surface plasmonresonance (SPR) experiments designed to accurately measure the affinity of two adamantanes - amantadine and rimantadine - to M2 ion channels.

They found two binding sites, affinities that vary by three orders of magnitude. This suggests that both binding sites are feasible, but it appears as though only the high-affinity binding site - a pore of the channel - is the site for pharmacological action

Drugs that target the lesser-affinity site - a lipid facing pocket - only have an effect in large concentrations by influencing the inhibitory action of the primary binding site.

While adamantanes are no longer effective and are not recommended for use, this research suggests that a new generation of anti-virals could be developed that target M2.

“Tamiflu and Relenza are the main drugs out there, but we can’t get too relaxed - resistance to Tamiflu is already evident,” said Dr Casarotto. “In a few years, those drugs may be ineffective, and we’ll be left with nothing frontline to fight an outbreak. This research paves the way for the next generation of drugs.”

The paper on their findings, ‘Coexistence of two adamantane binding sites in the influenza A M2 ion channel’, is published in the latest issue of Proceedings of the National Academy of Sciences (PNAS).