An analogue of the genetic letter, which causes many mutations in influenza viruses, can be effective against the new coronavirus.
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Once in the cell, any virus begins to synthesize its proteins and copy its nucleic acid. Then new copies of the viral genome will dress in structural viral proteins – new viral particles will form that will emerge from the cell. Moreover, viruses often have their own enzyme encoded in the genome, which builds copies of their nucleic acid. In the case of coronaviruses and a number of other RNA-containing viruses, this enzyme is called RNA-dependent RNA polymerase: it builds a new RNA molecule on one RNA molecule (template molecule) – it synthesizes polymer RNA from a variety of ribonucleotide monomers. RNA-dependent RNA polymerase is a purely viral invention; in RNA cells it is synthesized by DNA, and not by another RNA; so if we block the viral enzyme, we stop the virus from multiplying.
As it was said, viral polymerase uses ribonucleotides, so you can slip an analog molecule of some ribonucleotide into it so that the enzyme integrates the analog into the growing RNA and thereby causes multiple mutations in it, making the virus simply unviable. The use of nucleotide analogues, that is, analogues of genetic letters, is a common method that is widely used in all molecular biological laboratories where polymerase proteins synthesizing DNA and RNA are studied. Of course, if we want to use the nucleotide analog as a medicine, it is important that it interacts only with the viral enzyme.
Last October in Science translational medicine an article appeared about the EIDD-2801 molecule: in a cell, it turned into N4-hydroxycytidine – an analogue of one of the genetic letters associated with sugar ribose. It turned out that this analogue effectively suppresses the reproduction of influenza A and B viruses, and EIDD-2801 worked effectively not only in cell cultures, but also in sick ferrets (they are used in “flu” experiments because ferrets suffer from the flu just like humans )
Influenza viruses are also RNA viruses using RNA-dependent RNA polymerase. Can the molecule acting on them be used also against other RNA viruses with a similar enzyme? Just in the same Science translational medicine an article has been released that describes how EIDD-2801 works against coronaviruses. The authors of the first “flu” article, along with colleagues from the University of North Carolina at Chapel Hill, tested EIDD-2801 on human lung cells infected with the new SARS-CoV-2 coronavirus – and the analog molecule really suppressed virus reproduction in them.
In addition, EIDD-2801 was given to mice infected with two other known coronaviruses, SARS-CoV and MERS-CoV, the first of which caused an outbreak of SARS in 2002–2003, and the second caused a very dangerous Middle Eastern respiratory syndrome with 30% lethality; both viruses severely affect the lungs.
But if EIDD-2801 was given to mice between 12 and 24 days after infection, the viruses damaged the lungs much weaker, the virus particles themselves formed in the lungs less, and the mice lost less weight – that is, the disease was better tolerated.
The authors write that EIDD-2801 provoked many mutations in viral RNA, while the cellular RNA remained intact. (However, the safety of the EIDD-2801 will need to be double-checked – in February in the magazine Antimicrobial Agents and Chemotherapy an article came out that said that N4-hydroxycytidine may adversely affect RNA, which is synthesized in mitochondria.)
But EIDD-2801 is not the only analog of the genetic letter that they are trying to use against coronaviruses. More recently, we wrote about another such analogue called remdesivir, which blocks SARS-CoV-2 infection in human and monkey cell cultures and with which clinical trials are already underway in China and the USA.
However, viruses change rapidly, and they develop resistance to remdesivir – as, however, to EIDD-2801. But at the same time, if the virus develops resistance to remdesivir, it becomes more sensitive to EIDD-2801, and vice versa, so that both substances are likely to be used together – if the clinical trials of EIDD-2801, which are about to begin, will give positive results.
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