October 21, 2009
From adamantine therapeutics failures, interest in developing new drugs against the flu virus had come up. Hence, appeared oseltamivir and zanamivir, neuraminidase inhibitors, the first class of planned drugs against Influenza. Here, the path taken for their production was reverse of that of amantadine. Instead of testing the drug and finding out later how it works, a possible target was identified and then the drugs were made.
The target was Neuraminidase (NA), an enzyme that helps liberating the virus. When the newly-formed Influenza stems from the infected cell, its Hemaglutinine (HA) connects to sialic acid from the outside, through the same mechanism used by the virus to come in. But now it must not connect to the cell but get out of it. Neuraminidase recognizes those sialic acids and cleaves them, liberating the virus.
The development of zanamivir and oseltamivir benefited from this step. Both drugs mimic sialic acid but are not cleaved. Thus, they are recognized by NA which connects to them and are not able to attack membrane’s acids. 
Making use of this Neuraminidase affinity with sialic acid brings some advantages. First of them is the specificity, both drugs are very well recognized by viral enzyme, acting in Influenza A as well in B, and they are little recognized by human enzymes, reducing the odds of side effects.  Finally, as they imitate the enzyme natural substratum (molecule where it acts), loosing Neuraminidase its affinity with them implies in loosing affinity for our sialic acid. Thus, viruses with resistant NA are also less efficient, since they connect less to the drug and to the substrate. 
This does not mean that there are any resistant Neuraminidases. The most common resistance mutation is H274Y (or H275Y, depending on the NA type being used as reference), which means that the histidine amino acid has mutated into a tyrosine in position 275. It changes Neuraminidase’s interaction with oseltamivir, reducing its affinity to it. However, zanamivir interacts with other NA points and it is not reached by this mutation, which makes NA with H274Y resistant to oseltamivir and sensible to zanamivir.
There are other resistance mutations, including some with reduced susceptibility to zanamivir , but generally those jeopardize much the virus’ viability. Curiously, Influenza A (H1N1) is susceptible to oseltamivir and zanamivir, while the H1N1 strain that circulated between the end of 2008 and the beginning of 2009 in the US was almost 100% resistant due to the mutation H274Y .
Such knowledge on resistance mutation allows foreseeing which drug should be used or not. Even before starting treatment against Influenza A (H1N1), it was already known that the most probable resistance mutation in its Neuraminidase is H274Y. Thus, it was forecast that if a virus resistant to oseltamivir appears, it would be sensible to zanamivir .
And that was what happened, until October 02 when 28 resistance cases were found, all with H274Y. All cases were successfully treated with zanamivir, which is not usually the first drug of choice because it is inhalable, a course damaged in flu, while oseltamivir is orally taken.
But both drugs, adamantine and sialidase inhibitors do not guarantee any comfort. In the next post of this series, I will discuss the perspectives on new antiviral development.
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