The virus cannot replicate outside the cell. And when it enters a cell, it uses its resources for its own purposes: the cell copies the viral genome, synthesizes viral proteins, and all this at the expense of its own energy. Different viruses have different tools with which they distract the cell from its own interests and force it to deal with viral molecules. For example, the SARS-CoV and SARS-CoV-2 coronaviruses have a special protein that breaks down cellular RNAs. As we know, information from genes is copied into RNA, and then proteins are synthesized on RNA. If the cellular RNA is destroyed, then the molecular apparatus involved in the synthesis of proteins can be pulled onto coronavirus RNAs.
But the cell not only synthesizes new molecules, it also breaks down old ones. There are several mechanisms for cleaning up intracellular debris, one of them is autophagy, or self-eating, literally. With the help of autophagy, the cell processes not only old molecules, but also whole organelles that have ceased to work as they should, or which are simply no longer needed. Autophagy helps the cell get energy when the outside nutrients are scarce. In addition, by disassembling molecules and organelles for parts, the cell receives a building material for new molecules and organelles.
Different viruses have different attitudes towards autophagy. For example, it is stimulated by coronaviruses that live in animals. The human coronaviruses SARS-CoV-2 and MERS-CoV, on the contrary, are trying to slow down autophagy: it is believed that these viruses often fall into autophagic disassembly together with cellular molecules. That is, due to autophagy, human coronaviruses reproduce worse. Here the natural thought arises that if we increase autophagy in cells, we thereby ruin the life of the virus.
Researchers from the Berlin clinic “Sharite”, The University of Bonn and other research centers are described in Nature Communications experiments with several substances that could accelerate autophagy and suppress the reproduction of the new SARS-CoV-2 coronavirus. The first two of them are spermidine and spermine formed from it, molecules from the polyamine group. They have long been known to stimulate autophagy. Both are in our cells, in addition, spermidine is synthesized by bacteria of the intestinal microflora, and there is a lot of it in soybeans, mushrooms, and some cheeses. Finally, there are simply spermidine supplements.
In cells infected with coronavirus, spermidine inhibited virus multiplication by 85%, and spermine by 90%. But in experiments they were used in very high concentrations and not in the form in which both substances are used for medical purposes. Of course, both spermine and spermidine are already present in our tissues, and both are natural polyamines. But all the same, the question arises whether there will be side effects from them if they float in the blood in the concentration that is needed to fight the coronavirus. In addition, the coronavirus itself uses spermine and spermidine to reproduce, so the problem of the therapeutic dose is further complicated.
The third substance that enhances autophagy and suppresses the virus is experimental drug MK-2206. It acts on an enzyme in one of the cellular signaling pathways, and MK-2206 was originally developed as an anti-cancer agent. But, as it turned out, the same molecule is able to reduce the production of new viral particles by 90%.
However, the most promising in this sense turned out to be niclosamide – a medicine for parasitic tapeworms. By stimulating autophagy, it suppressed the multiplication of SARS-CoV-2 by as much as 99%. In fact, niclosamide has already been studied for its anti-coronavirus properties and has shown good efficacy against the MERS-CoV virus, the causative agent of the Middle East acute respiratory syndrome and a cousin of the current SARS-CoV-2.
Niclosamide is supported by the fact that it turned out to be the most effective of all four substances, and that it has been used in medicine for a long time (that is, its possible side effects and behavior in the human body have been sufficiently studied), and that sky-high doses of the drug are not required for the antiviral effect. On the other hand, experiments have so far been performed only on cell cultures – and now the anticoronavirus abilities of niclosamide need to be tested in clinical trials.
Source: Автономная некоммерческая организация "Редакция журнала «Наука и жизнь»" by www.nkj.ru.
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