Oseltamivir/Tamiflu (Part 2: Neuraminidase: Viral glue remover)
3rd May 2006
Yesterday, we started in on Tamiflu. From the previous article:
A lot of people have been interested in it because it’s likely to be helpful against the “bird flu” strain of the H5N1 influenza subtype. Specifically, the concern is that bird flu might mutate into a form that is transmissible between humans. Today, some humans have gotten it - however, we don’t know of anyone who got it from a human - it’s occurred only in humans who work closely with birds.
Today, we’ll talk about its biochemistry. Back to the structure:
Why is this useful against flu? To understand, we take a look at an enzyme expressed by flu viruses: neuraminidase. Here’s a “ribbon diagram” - a 3-D simplified structure that helps us understand how an enzyme is shaped:
Neuraminidase structure. Image courtesy NASA (public domain), from Wikipedia article.
Neuraminidase cleaves sialic acid residues. Sialic acid is crucial to the process of budding in the viral cycle. Its cleavage allows the release of a membrane-enclosed virion - it means that the new viruses from an infected cell can go on to infect more cells. It goes something like this:
- Viral particle taken up into cell
- Viruses replicate and assemble (Antivirals like AZT work here)
- Virus particles are released from the cell. Cleavage of sialic acid by neuraminidase is crucial here (Antivirals like Tamiflu work here).
- Newly released virus particles participate in (1).
The structure of sialic acid is shown below.
Here is a cartoon demonstrating how the cycle works. So, why is Tamiflu so special?
Take a look at the six-membered ring and the relative positions of the electronegative atoms (nitrogen and oxygen). Tamiflu is a structural analogue of sialic acid. The idea is, drugs like Tamiflu bind to neuraminidase better than sialic acid. If the neuraminidase is busy binding drugs, it can’t do it’s virus-releasing business. We have some other drugs, Zanamivir (Relenza) probably being the best-known.This “finding an analogue that fits in an enzyme pocket” business is a huge part of drug design.Why the concern over people stockpiling? The concern is akin to that of antibiotic misuse. Right now, neuraminidase inhibitors work okay. If a mutation occurs in the flu virus that makes it resistant to Tamiflu (for example, Tamiflu doesn’t fit as well in the enzyme’s “pocket”), we might be in trouble. How prevalent neuraminidase inhibitor -resistant strains of flu will be remains to be seen. Some people have suggested we might see people jumping the gun and taking their Tamiflu, causing a spike in resistance in nonavian influenza. (Perhaps not that likely, considering how hard it is to get a hold of, people might not be so inclined to use it at the drip of a nose).
What’s encouraging is the fact that resistant mutant strains (of virus or bacteria) tend to be less fit than the “wild-type.” In the absence of antibiotics or antivirals, the mutants are usually wasting energy busy making whatever makes them resistant, or their neuraminidase doesn’t work as well. When drug misuse is discontinued, resistant strains almost always disappear, because the wild-type outcompetes them.