In the case of a pandemic, and during the seasonal epidemics, once a person has already contracted the influenza, we can do little, other than monitor and treat him with antivirals. However, they are not always a guarantee of success, especially in the case of resistant viruses.

ResearchBlogging.orgAmantadine and rimantadine are the first drugs used against influenza, still from a time when drugs were tested previously and before its effects were discovered [1] – it may seem strange to make this comment but the difference will soon be clarified. They act by inhibiting the action of the M2 protein.

When the Influenza enters a cell, it uses the cell’s normal metabolism for itself. Thus, to unwrap itself in the right place, its proteins are only detached from one another, releasing the genes that will invade the nucleus only when the virus is in the right place, and it measures its position through the pH of the endosome, the sack of the membrane it forms when entering.

Proteína M2 sevindo de canal para os íons H+ acima. Desempacontamento do vírus e liberação dos genes abaixo.

M2 Protein serving as a channel for the H+ ions, above. Unwrapping of the virus and release of the genes, below.

When the endosome moves towards the inner part of the cell, its pH is reduced.  It is only in this acidic pH that the influenza releases its genes, ensuring that it is close to the nucleus. Protein M2 is responsible for generating this signal by forming a pore on the membrane of the virus allowing the H+ ions that generate the acidic environment to enter the virus. Amantadine makes the M2 to remain closed and prevents the formation of the pore through which the H+ ions enter, inhibiting the virus from becoming more acidic and unwrapping its proteins.

Although they are efficient, the adamantanes have some problems. The first of them is that they are neurotoxic, attacking the central nervous system as side effect. After all, our nervous system also depends on the pores that give way to ions. The second and the biggest problem is the resistance.

Amantadina em vermelho, bloqueando o poro formado por M2. Com isso, a proteína M1 não se desliga dos genes do vírus (acima) e eles não podem invadir o núcleo celular.

Amantadine in red, blocking the pore formed by M2 and preventing the H+ ions from entering the virus. With this, the M1 protein does not detach from the genes of the virus (above) and they cannot invade the cell nucleus.

Due to the type of interaction that occurs between M2 and the adamantanes, the M2 proteins can undergo mutation, which makes it resistant to these drugs without losing its activity. The most common mutation is the S31N, which means changing  a serine by an asparagine in position 31, or better still, the number 31 serine amino acid at the start of the protein, changes to an asparagine. With this change, the M2 protein loses stability when closed and it can open up and form the pore even with the amantadine attached. The virus is now resistant to these drugs and even in their presence it can unwrap itself. [2]

With the inappropriate use of the antivirals, wrong doses, prescriptions for those who do not need it, prescriptions for people with another respiratory virus, the appearance of resistant viruses is highly favored. After the appearance of the H5N1, the bird flu virus, and consequently the fear caused in the population, the search for antivirals grew considerably, giving way for this to occur more easily.

In the United States, the frequency of the adamantane-resistant influenza in the flu season at the end of 2003 – beginning of 2004 was 1.9%.  Between 2004 and 2005 it increased to 14.5% and in 2005 and beginning of 2006 it reached the alarming frequency of 92% of the circulating H3N2. Almost all due to the mutation in the residue 31. [3]

All the Influenza B are resistant to adamantanes, and in the case of influenza A (H1N1), which inherited an M2 from the swine virus circulating in Europe and Asia, amantadine and rimantadine also have no effect. [4]

Fontes:

[1]Davies, W., Grunert, R., Haff, R., McGahen, J., Neumayer, E., Paulshock, M., Watts, J., Wood, T., Hermann, E., & Hoffmann, C. (1964). Antiviral Activity of 1-Adamantanamine (Amantadine) Science, 144 (3620), 862-863 DOI: 10.1126/science.144.3620.862
[2] Pielak, R., Schnell, J., & Chou, J. (2009). Mechanism of drug inhibition and drug resistance of influenza A M2 channel Proceedings of the National Academy of Sciences, 106 (18), 7379-7384 DOI: 10.1073/pnas.0902548106
[3] Weinstock, D. (2006). Adamantane Resistance in Influenza A JAMA: The Journal of the American Medical Association DOI: 10.1001/jama.295.8.jed60009
[4] . (2009). Emergence of a Novel Swine-Origin Influenza A (H1N1) Virus in Humans New England Journal of Medicine, 360 (25), 2605-2615 DOI: 10.1056/NEJMoa0903810