"We are counting on a double effect"
Scientists – about the destruction of the coronavirus
Tatiana Pichugina, RIA Novosti
Russia is developing drugs for the prevention of coronavirus infection based on RNA interference. This is a completely new approach that simulates the intracellular processes of fighting viruses in plants and animals. RIA Novosti was told about this by the director of the I. I. Mechnikov Research Institute of Vaccines and Serums, corresponding member of the Russian Academy of Sciences Oksana Svitich and the head of the Laboratory of Molecular Virology, Candidate of Biological Sciences Evgeny Fayzuloev.
Experiments with coloring
In the early 1990s, the American company DNA Plant Technology tried to bring out petunias of a richer purple color. Scientists have inserted a chimeric gene into the DNA of plants that enhances the synthesis of a natural dye. But, contrary to expectations, more than half of the genetically modified petunias grew up white. This means that the desired gene was not activated, but, on the contrary, was silenced. Why – the authors of the experiment did not understand.
A few years later, Andrew Fire from Stanford and Craig Mallow from the University of Massachusetts were looking for genes regulating the early development of the nematode worm Caenorhabditis elegans. To turn off a certain section of DNA, RNA molecules were injected.
In cells, RNAs perform many functions, but the main one is reading information from DNA, transmitting instructions for protein synthesis. Such RNAs are called semantic. Antisense RNAs, on the contrary, drown out genes. It was with them that Fire and Mallow worked. They discovered and explained the natural mechanism of switching off too active genes – RNA interference. For this, they were awarded the Nobel Prize in 2006.
microRNAs regulate genes
RNA interference allows you to disable a section of the genome without editing it. Strictly speaking, organisms obtained in this way are not considered genetically modified. An example is star–colored petunias.
"The point here is to suppress the expression of a gene at the stage of transcription or translation, the specificity of which is determined by small RNA molecules complementary to matrix RNA (mRNA)," scientists from the I. I. Mechnikov Research Institute of Vaccines and Serums explain.
To synthesize a protein in a cell, information about it is transferred from a certain section of DNA to RNA (called matrix). This is the transcription stage. Then the RNA enters the ribosome, where instructions are read from it and protein synthesis – translation begins. If transcription or translation is disrupted, the protein is not synthesized. To do this, you need to send a special RNA into the cell, which will intercept the matrix and prevent it from working normally.
A kind of cocktail of synthetic RNA molecules is introduced into the body, which serve as a substrate for the formation of short interfering RNAs (Kirnas) and together with proteins, primarily Argonaute2 – argonauts proteins, create a complex molecular complex. The RNA in it contains complementary sections, that is, corresponding to the code of the matrix RNA. The complex binds and neutralizes it. The protein is not synthesized.
"The functions of RNA interference have changed along with the evolution of the organic world. So, in plants, insects and roundworms, it forms antiviral immunity. As the genome became more complex, this mechanism was increasingly involved in the regulation of transcription and translation," the experts note.
In the body, RNA interference is provided by two types of molecules – microRNA and piRNA. A link has been established between the malfunction of microRNAs and hereditary diseases, cancer, heart and nervous system diseases. According to the British miRBase database, 1917 microRNA genes were found in humans, and 1234 in mice. piRNAs protect the genome from mobile genetic elements.
Against cancer and viruses
In RNA interference, we immediately saw a great potential for practical application. Medicine has received a tool for the treatment of rare hereditary diseases caused by a mutation of one or two genes.
In 2001, scientists from the Institute of Biophysical Chemistry of the Max Planck Society (Germany) showed that double-stranded RNAs with a size of 21 bases are the most effective. They are easy to synthesize and modify, which opened up wide opportunities for the creation of drugs.
In 2018, the USA approved the first drug based on RNA interference - patisiran for the therapy of transtiretin amyloidosis. This is a hereditary disease in which the protein transtiretin accumulates in the cells, which leads to death in childhood. If a solution of modified siRNAs is injected intramuscularly in time, the development of the disease slows down significantly. A cure for acute hepatic porphyria is on the way, acting on the same principle.
RNA interference protects insects and roundworms from viruses. There is no human being, but science can fix it.
One option is to turn off the genes of the virus so that it does not replicate inside the cell. This path was followed at the Institute of Immunology of the FMBA of Russia, where the MIR-19 drug is being developed. However, the viral genome mutates rapidly.
Another way – to turn off genes in a cell infected with a virus – was used at the Mechnikov Research Institute of Vaccines and Serums. In this case, you don't have to worry about the evolution of a particular strain.
"Viruses are obligate intracellular parasites. They need cellular factors and signaling pathways to ensure the reproduction cycle. With the help of kiRNA, these processes can be blocked," the scientists specify.
It is believed that SARS-CoV and SARS-CoV-2 easily penetrate the cell's defenses due to proteins that suppress RNA interference. In particular, nucleoproteins N and 7a. Their genes were chosen as targets for kirnas. "Here we are counting on a double effect – a decrease in the infected cells of the products of these genes and a decrease in the effect of suppression of RNA interference," the interlocutors of RIA Novosti add. Another possible target is the genes of membrane proteins that facilitate the virus to enter the cell, ACE–2 and neuropilin 1.
NIIVS is currently experimenting with cell lines infected with various viruses. The results are encouraging, and given the speed at which new drugs are being tested and put into circulation, there is a chance that a coronavirus spray will appear in the near future. It is enough to treat their nasopharynx before leaving the house – and the infection is powerless.
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