Drug that tricks the flu
With winter approaching, here’s a piece of good news. A new, experimental drug that can knock-out flu and other viruses has been developed by scientists in America. Called EIDD-2018, it works by mimicking one of the ‘letters’ that make up the virus’ genetic code. When the virus grows, it accidentally uses the drug molecule instead of its own genetic letter, introducing genetic ‘spelling mistakes’ that are lethal for the virus. Cambridge University’s AJ te Velthuis, who studies how viruses grow but wasn’t involved in the present research, took Chris Smith through what the US team have done…
AJ - Flu is a massive problem for human health and also for our economy. We have vaccines but they're only 20 to 60 percent effective, and the virus still kills a lot of elderly and young people every year. We have some antivirals, but the virus is constantly getting resistant to them. So we need a new drug that can help us fight a new pandemic.
Chris - And some of these antiviral drugs are not actually that good, are they? They're not the viral equivalent of when you give penicillin to someone with meningitis and save their lives. These drugs, they work a bit but they're not brilliant.
AJ - Exactly, they're not very effective. And as I said, the virus can get quite easily resistant to them and then their efficacy is completely gone. This group has been looking to find a nucleotide analogue. So the viral genome consists of nucleotides. They have names and usually they’re abbreviated as A, G, C, and U.
Chris - These are genetic letters?
AJ - These are indeed genetic letters. And the drug mimics the C letter. The virus can incorporate that into its genome; this results in a mutation, and this can lead to misfolding of viral proteins, or even completely not-working proteins.
Chris - I get it. So you would give cells that are infected with the flu this molecule, and when the virus is making copies of its genetic information it mistakes this one - that’s the drug - for the chemical it should be putting in, and it messes up the sequence of the viral genetic information.
AJ - That is correct.
Chris - How have they tested it so far?
AJ - So they've tested it in a number of ways. What the scientists first did was add a drug to cells growing in a petri dish. Normally the virus would kill these cells, but in the presence of the drug it wasn’t able to. The cells were basically healthy and cured. Next they moved to animal experiments, ferrets that they also gave the drug to. Normally when these ferrets get infected with the virus they develop fever, start coughing, sneezing; but in the presence of the drug the fever disappeared much more quickly and they didn't have as much virus particles in their airway system.
Chris - And critically, were the animals harmed by the drug? Because one’s always very worried about side effects - all drugs have side effects.
AJ - They didn't see evidence for this. The cells remained healthy in the presence of the drug for a very long time.
Chris - One of the issues with treating the flu is that the viruses evolve to become resistant to drugs, in the same way the bacteria evolve to become resistant to antibiotics. Did that happen here? Did the tests on the cells in the dish or on the ferrets actually produce any viruses that were resistant?
AJ - So that's a very good question. There is evidence that influenza can get resistant to drugs like this new one, so they did specific experiments to test this. They added virus to cells containing the drug and looked for resistance mutations; and they didn't find any. So that is very, very promising.
Chris - Do we know why?
AJ - It could be that it is very difficult for the virus to make a resistant mutation. Maybe it needs to mutate at a couple of sites at the same time to be able to cope with the drug. And that just takes time, and that wasn't seen or mimicked in this experiment.
Chris - Why is the virus fooled by this drug that it accidentally shoves into its genetic information, and our own cells - which also have genetic information on them using similar chemicals - aren’t?
AJ - This drug is incorporated by an enzyme called a polymerase. And all cells and all viruses have polymerases, but they're all slightly different. And it seems that drug just binds better to the flu polymerase than to a human one.
Chris - And do you think that the differences that they saw in the ferrets would actually be clinically significant? So if that were a patient, and a patient responded the same way the ferrets did, that actually this would translate into a real benefit clinically?
AJ - So in their experiments they took along a control, and that control is currently available over the counter: it's Tamiflu. And what they saw in the ferret experiments was that their drug works better at reducing fever and minimising clinical symptoms than Tamiflu. So that is very promising.
Chris - One of the attractions of Tamiflu is: you can pop a pill. You don't have to inject this stuff. Is it the same for this drug or would this be an injection?
AJ - In theory this could also be provided in the form of a pill.
Chris - And cheap? Easy to make?
AJ - That, I don't know.
Chris - That's a question of wait and see then.
AJ - Exactly. Although I would predict that this could be cheaply made. It's a small molecule so it could be scaled up quite easily.