09-26-2013, 08:43 AM
Mutation of influenza virus M2 proton channel and drug resistance
The previous article focuses on how the anti-viral drug amantadine targets the M2 proton channel of the H1N1 influenza A virus. However, one of the major issues with designing effective anti-viral drugs is the constant mutation of viruses which can render once effective drugs relatively powerless. This has been the fate of amantadine and another adamantane-based drug, rimantadine. Both of these drugs formerly had a 90% bioactivity against H1N1 influenza A virus, however this has been lost due to viral mutation rates, mainly at sites S31N, V27A and L26F in the channel pore. Thus there was a necessity to develop new anti-viral drugs against the M2 channel. Availability of the NMR structure of the M2 channel, as referred to in the previous article, provides the structural basis for design of such drugs. This NMR structure provided information on the M2 channel gating mechanism and the inhibiting mechanism.
New adamantine-based inhibitors were designed which hold two adjacent helices of the H1N1-M2 tetramer via two inhibitor pharmacophore groups outside the channel. Such newly designed inhibitors are hoped to address the problem of H1N1 influenza A virus drug resistance. Work is ongoing in designing new adamantane-based drugs, for example polycyclic amines initially designed as ring-rearranged analogues of amantadine. Some of these secondary amines had inhibitory activity against influenza A M2 function. It was observed that some H1N1 viruses such as the A/PR/8/34 strain are particularly sensitive to the kind of subtle increase in endosomal pH caused by the amines.
There are issues associated with advancing drugs directed against the mutated M2 channels to clinical trial. These issues include lack of a robust assay for discovery of new candidates. Recently, a yeast growth restoration assay has been proposed as a potentially robust and sensitive high-throughput screen for M2 channel inhibitors. Results were promising as in a screen of over 250,000 pure chemicals and semi-purified fractions, 21 active compounds were identified which included comprising amantadine, rimantadine and 13 related adamantanes. In addition some non-adamantanes were identified including hexamethylene amiloride and a triazine derivative. The search continues for effective drugs against mutated H1N1 influenza A virus M2 proton channels, but there are promising signs.
Sources
BALGI, A.D. et al., 2013. Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay. Plos One, 8(2), pp. e55271-e55271
DU, Q. et al., 2010. Designing inhibitors of M2 proton channel against H1N1 swine influenza virus. Plos One, 5(2), pp. e9388-e9388
TORRES, E. et al., 2013. Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds. Antiviral Research
The previous article focuses on how the anti-viral drug amantadine targets the M2 proton channel of the H1N1 influenza A virus. However, one of the major issues with designing effective anti-viral drugs is the constant mutation of viruses which can render once effective drugs relatively powerless. This has been the fate of amantadine and another adamantane-based drug, rimantadine. Both of these drugs formerly had a 90% bioactivity against H1N1 influenza A virus, however this has been lost due to viral mutation rates, mainly at sites S31N, V27A and L26F in the channel pore. Thus there was a necessity to develop new anti-viral drugs against the M2 channel. Availability of the NMR structure of the M2 channel, as referred to in the previous article, provides the structural basis for design of such drugs. This NMR structure provided information on the M2 channel gating mechanism and the inhibiting mechanism.
New adamantine-based inhibitors were designed which hold two adjacent helices of the H1N1-M2 tetramer via two inhibitor pharmacophore groups outside the channel. Such newly designed inhibitors are hoped to address the problem of H1N1 influenza A virus drug resistance. Work is ongoing in designing new adamantane-based drugs, for example polycyclic amines initially designed as ring-rearranged analogues of amantadine. Some of these secondary amines had inhibitory activity against influenza A M2 function. It was observed that some H1N1 viruses such as the A/PR/8/34 strain are particularly sensitive to the kind of subtle increase in endosomal pH caused by the amines.
There are issues associated with advancing drugs directed against the mutated M2 channels to clinical trial. These issues include lack of a robust assay for discovery of new candidates. Recently, a yeast growth restoration assay has been proposed as a potentially robust and sensitive high-throughput screen for M2 channel inhibitors. Results were promising as in a screen of over 250,000 pure chemicals and semi-purified fractions, 21 active compounds were identified which included comprising amantadine, rimantadine and 13 related adamantanes. In addition some non-adamantanes were identified including hexamethylene amiloride and a triazine derivative. The search continues for effective drugs against mutated H1N1 influenza A virus M2 proton channels, but there are promising signs.
Sources
BALGI, A.D. et al., 2013. Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay. Plos One, 8(2), pp. e55271-e55271
DU, Q. et al., 2010. Designing inhibitors of M2 proton channel against H1N1 swine influenza virus. Plos One, 5(2), pp. e9388-e9388
TORRES, E. et al., 2013. Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds. Antiviral Research
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