Tamiflu

I’ve been pretty lucky over the past year, and have not been infected with the dreaded swineflu. Some of the guys in my office have had it I think (or maybe it was just a mild case of manflu), but I have thus far escaped the contagion. Despite these ‘flu’s not being as bad as predicted though, I thought taking a look at how Tamiflu works might be an interesting ‘MOTM’.  Given all the media hype about Tamiflu, and the fact that many of you reading this might have been taking the drug, (and that you might not have even heard of it this time last year) it should be quite relevant.

So I guess first we need to discuss what causes Swineflu. It’s a virus, known by the now scary sounding H1N1 code name. Just like vines are tree parasites, viruses are parasitic upon human cells; they use them as a host in which to reproduce. To do this, one of the many important things they need to remember to do is to properly tether themselves to the cell. They use a protein (hemagglutinin) to do this. The protein has an internal cavity which is just the right shape to bind to sialic acid, a type of sugar molecule which is present on all our cell surfaces. Once the virus has done it’s dastardly work, it would early love to release itself from the depleted host and stroll on down the road on the look out for a new cell to devour. The link between hemagglutinin and sialic acid is quite strong though (afterall, the virus doesn’t want to just float away mid-infection) and so the virus must be able to cut itself free.

Analogies can only take us so far though. The virus doesn’t really ‘cut itself free’ as such. Rather, it produces a second protein which binds to the sialic acid too. This displaces the hemagglutinin tether and releases the virus from the cell. This second binding protein is called neuraminidase.

220px-Neuraminidase_Ribbon_Diagram

Viral neuraminidase with bound sialic acid

 Figure 1 – Neuraminidase with sialic acid derivatives

Neuraminidase is what drugs like Tamiflu target. They stick inside the hollow cavity of the enzyme (figure 1), blocking it, so that it can’t get hold of the real sialic acid. This means viruses can’r properly detach, therefore they spread around the body less quickly. Tamiflu doesn’t actually kill the viruses, it just makes it more difficult for them to multiply quickly.

This has lead to some debate about whether it’s really worth taking Tamiflu in the first place. Certainly, the advice is not to bother if you’ve had symptoms for more than a few days. By the time you get things like aching muscles, neausea and headaches the infection has spread far and wide across your body, and your immune system will be in the process of dealing with it already. Where drugs like Tamiflu are useful, is if you’ve been in such close contact with a person who has blatently has the ‘flu (say a spouse or housemate) that you’re sure you’ll come down sick next. In this case, taking neuraminidase inhibitors can stop you ever developing symptoms. This does have the downside that you don’t get to spend a couple of workdays wrapped in a duvet in front of ‘this morning’ though.

Since the neuraminidase cavity is specially shaped to be complimentary to sialic acid you might imagine that the drug must have quite a similar shape. In fact it does. Although the functional groups (that is the way the atoms are connected together) is not exactly the same, the general shape and topology of the molecule is very similar, as shown in figure 2. 

 

Figure 2 –  Oseltamivir (‘Tamiflu’) and sialic acid have similar chemical structures. 

 

Scientists fear though that viruses will quickly adapt to be resistant  to Oseltamivir. The process of evolution is much quicker in single-celled organisms since they reproduce much more quickly than humans. Instead of a matter of decades, the next virus generation can be ‘born’ in only minutes. This means that just like the battle to continuously create new antibacterials, scientists need to keep developing slightly modified versions of the Tamiflu molecule, which – hopefully – will remain effective against flu for  at least  a while. One example of this is GlaxoSmithKline’s Zanamivir (trade name, Relenza). Figure 3 shows that, again, it has a shape which is pretty reminiscent of sialic acid.

 

 

Figure 3 – Zanamivir (‘Relenza’)

 

Note

Some of the diagrams in this post are drawn in a language native to organic chemists (like me). These skeletal formulae are an effective way of communicating the 3D structure of molecules in a 2D representation. They can be confusing though. If you’d like to learn more about them, keep a look out for the new page on B21 explaining more about how they work (currently under construction).

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One Response to Tamiflu

  1. Nicky says:

    Very interesting Josh 🙂

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