Against all strains of influenza A

Is it possible to make a universal medicine against the flu

Kirill Stasevich, Science and Life (nkj.ru ) based on materials Science.

We protect ourselves against infectious diseases with vaccines: immunity is presented with dead or half-dead pathogens, or some characteristic molecules by which they can be recognized, and immune cells remember the antigens of the pathogen.

Then, when a virus or a bacterium appears in the body, immune cells will quickly "remember" them and synthesize a lot of necessary immunoglobulins-antibodies that will interact with this pathogen. Antibodies bind to viruses and bacteria, as well as to infected cells, on the surface of which there are proteins from viruses and bacteria, making them visible to immune killer cells; in addition, the antibodies themselves prevent foreign molecules from performing their functions. As a result, the immune system will quickly suppress the disease, not allowing it to unfold in full force.

However, there are pathogens to which there is still no sufficiently effective vaccine – one that could be administered once and forget about the disease for many years. One of these pathogens is the influenza virus. We have to be vaccinated against the flu virus every year, and each time the vaccine is not the same as it was last year. That's because the virus mutates easily, and the strain that appears in the new year is somewhat different from last year. But the immune system remembers exactly last year, and therefore the new virus remains partially invisible: those anti-flu antibodies that the immune system can start making immediately are tuned against several other viral proteins, those that were relevant a year ago. It is impossible to predict which kind of flu will appear next time, so there is still no universal vaccine against "flu in general". Actually, even in each season, people can get sick with different strains of influenza, among which there will be very common and not very common.

In the case of influenza, the immune system is tuned against the hemagglutinin protein, with which the virus interacts with the cell. Just hemagglutinin in influenza changes very much. However, at the same time, there are very conservative sites in its molecule, which look the same in different strains – if the conservative site of hemagglutinin changes, the virus will not be able to dock to the cell and penetrate into it. Usually, the immune system produces antibodies against volatile parts of hemagglutinin, and such antibodies work only against one strain. But a few years ago, people were found to have so-called broad-spectrum antibodies that grab the viral protein by conservative areas that are the same in different strains.

Maybe patients should just be given such antibodies so that they block the viral protein and prevent the virus from entering the cell? The antibodies themselves are very large, and they are quite difficult to obtain. But on their basis, it was possible to construct a much smaller protein that adhered to the viral hemagglutinin in the same conservative areas, and therefore could work like real antibodies.

However, even such a small protein is not very convenient from a medical point of view: if we want to get some kind of pill that we just need to put in our mouth and swallow, then if the active substance in it is protein, it will simply be broken down by digestive enzymes. That is, we need to think about how to protect the drug from splitting, to give it time to be absorbed into the blood.

Researchers from the biotechnology companies Janssen Pharmaceutical Companies and the Scripps Institute did otherwise – in an article in Science (van Dongen et al., A small-molecule fusion inhibitor of influenza virus is orally active in mice), they describe a non-protein substance that binds to the hemagglutinin of the influenza virus in the same places and as strongly as the aforementioned broad-spectrum antibodies. A complex molecule of six rings was searched for in a library consisting of 500,000 chemical compounds, about 9,000 hopefuls were selected among them, and among them they have already found the only one that fit best.

Hemagglutinin of the influenza virus and the molecule JNJ4796, which prevents conformational changes in a certain area (fusion peptide). A drawing from an article in Science.

Connecting with hemagglutinin, the JNJ4796 molecules immobilize it, as it were: in order for the virus to enter the cell, hemagglutinin must change shape, but, hung with medicine, it cannot do this. Experiments with cell cultures have shown that JNJ4796 does not allow the virus to enter either mouse cells or human cells. Moreover, if mice were fed JNJ4796, they remained alive despite the lethal dose of the virus. Both in experiments with cells and in experiments with mice, different strains were used, so this substance can be called an almost universal cure for influenza.

Almost – because there are varieties of the virus against which JNJ4796 does not work. For example, JNJ4796 does not work on influenza type "B". Influenza B epidemics develop more slowly and occur less frequently, but you still need to protect yourself from them. Most likely, if JNJ4796 enters clinical practice, it will be used with other means, for example, with the same vaccines.

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