Influenza A(H3N2): the return of Adamantane

Around 1933, adamantane was discovered in petroleum. Because the content of it varies from between 0.0001% and 0.03%, it is far too low for commercial production. Which means it has to be synthesized in a laboratory.

All medical applications known so far involve not pure adamantane, but its derivatives. The first adamantane derivative used as a drug was amantadine in 1967. It was prescribed as an antiviral drug for the prevention and therapy of various strains of influenza A[1]. Other derevitives followed. Rimantadine was believed to inhibit influenza's viral replication, possibly by preventing the uncoating of the virus's protective shells, which are the envelope and capsid.

However, effectiveness of both amantadine and rimantadine was lost when Influenza A viruses acquired an amino acid substitution at one of five critical residues of the M2 protein[2]. It was thought these antiviral drugs would be consigned to history.

But, when doctors stopped prescribing these drugs, the pressure on the viruses diminished: they 'thought' that the previous mutation wasn't useful anymore and the mutation was lost in favour of other mutations that were more useful.

Even though the Influenza A(H3N2) virus has continued to undergo substantial antigenic and genetic evolution over the last decade, the M2 residue has remained almost completely fixed, suggesting that during that time it contributed to viral fitness. However, the recent detection of M2 S31 and D31 viruses in Australia suggests that the importance of the M2 N31 residue in viral fitness may no longer be as strong as it was[3].

It may be that the M2 S31 viruses detected in Australasia in 2017 could be the progenitors for a reversion back to more widely circulating adamantane-sensitive Influenza A(H3N2) viruses, some 12 years after the resistant strain emerged and then dominated globally. If this were the case, it would revive the option of using adamantanes to treat Influenza A(H3N2) virus infections and improve the opportunities for using these drugs in combination with other antivirals[4].

[1] Maugh: Panel urges wide use of antiviral drug in Science – 1979
[2] Hayden et al: Emergence and transmission of influenza A viruses resistant to amantadine and rimantadine in Current Topical Microbiology and Immunology - 1992
[3] Beigel et al: Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial in Lancet – 2017
[4] Hurt et al: Detection of adamantane-sensitive influenza A(H3N2) viruses in Australia, 2017: a cause for hope? in EuroSurveillance - 2017