You hit the virus hardest in his RNA

Pers / media: OverigPopular

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Vaccines, antibodies and various antiviral agents invariably target the proteins of the coronavirus SARS-CoV-2. But the virus’ weakest spots lie deeper, thinks molecular geneticist Danny Incarnato of the University of Groningen. The virus can be hit hardest in its RNA, the genetic material, says Incarnato. “The vulnerability is not so much in the precise letter order of the genetic code, but in the three-dimensional structure of the hereditary molecule. If the RNA is not folded correctly, the virus cannot start anything. ” 

The originally Italian scientist has had his own research group in Groningen, the “IncaRNAto lab”, according to his website for eighteen months. Together with groups in Warsaw and the LUMC in Leiden, he writes in an article that appeared in the trade journal earlier this month Nucleic Acid Research a whole new approach to virus infection. Based on the spatial structure of the RNA molecule, the team accurately analyzes where new drugs could act. The research revealed dozens of potentially sensitive spots in the virus RNA. 

 

Yes, rna as a drug target is still relatively new, Incarnato says. “Our field is at least twenty years behind the regular drug development that focuses on proteins. But interest in this approach is growing from the pharmaceutical industry, especially now that the first drugs of this type are on the market. ” This summer, for example, the US FDA approved Risdiplam, an RNA drug for a rare muscle disease. 

Long streak of information

“By the way,” adds Incarnato, “anyone who thinks this is all very exotic should remember that many antibiotics already work that way. Streptomycin, for example, settles in the RNA of the ribosome, disrupting the production of proteins in bacteria ”. 

The SARS-CoV-2 genetic code consists of a single-stranded RNA molecule of approximately 30,000 letters (nucleotides). However, it is not just a long string of information, Incarnato explains. Yes, it contains the information for all the proteins that the virus needs to take control of protein production in the infected cell. But the virus cannot hijack the host cell with proteins alone; the correct three-dimensional shape of the turns of the rna is also essential. 

 

The rna chain frequently folds back on itself, with the nucleotides that match each other forming a double strand. This creates strange curves, branches and hairpins. That is not an accidental messy tangle, like adhesive tape that curls up stubbornly, Incarnato explains, “it is just as functional for the virus as the code for proteins”. 

Valuable starting points

Some RNA structures are so “sacred” that the virus cannot live without them. The spatial form directs essential processes for the virus, such as the production of proteins and the assembly of new virus particles. “That makes this valuable starting points for virus control.” 

Incarnato and his team searched for so-called pockets, small cavities in the three-dimensional structure of the RNA. These arise in places where opposite rna chains do not fit neatly together. A small molecule could fit into these pockets, disrupting the standard folding of the RNA. With any luck, that will shut down crucial tasks of the virus in the cell. “Drugging the rna”, Incarnato calls it. 

 

Exactly how the rna folds can be determined with the help of the computer. It calculates of all possibilities which conformation is energetically most favorable. This has to be done in small pieces, because computers are not yet powerful enough to calculate the folding of the entire genome in one go. 

The Italian then put on evolutionary glasses to determine which pockets in the RNA have an indispensable function for the virus. To this end, he looked for related structures in other coronaviruses from the same family as SARS-CoV-2. He found 87 stable regions in the RNA of coronaviruses, an indication that these structures are indispensable for the functioning of the virus. 

They mutate quickly

To make sure he got hold of segments that are essential because of their conformation and not coincidentally because they encode an important protein, he refined the selection by looking for covariation of opposite nucleotides. That is, if one nucleotide changes due to a mutation, the opposite nucleotide will also have to change, otherwise the folding of the rna will change. 9 of the 87 stably folded segments met that condition. In each of these there are at least one but sometimes as many as three pockets where an RNA drug could reach. 

A virus would not be able to escape from such a drug, says Incarnato. RNA viruses mutate rapidly and can therefore become resistant to vaccines and antibodies with minor changes. But if they are caught on the essential fold of the rna, they are much less able to do something about it. 

 

 

 

I cannot promise we will find such a drug anytime soon 

 

 

 

Danny Incarnate geneticist

 

 

 

It is difficult to predict which substances can put a stick in the spokes of the virus in this way. “That’s a matter of it trial and error”Says Incarnato. “Just try to find out which molecules are going to get into the RNA holes. We work with John Schneekloth’s American group at the National Cancer Institute. They have developed a method with which we can screen thousands of molecules quickly and on a large scale. If a candidate is found, it must then be examined whether it works as a virus inhibitor. I cannot promise that we will find such a drug quickly, but I like to be optimistic. ” 

Is Incarnato not afraid that such a drug will come much too late, now that various vaccines against the coronavirus are already on the way? “Better safe than sorry”, He says with a shrug,“ There is also a chance that vaccines will not work well. Plus, people who refuse to be vaccinated and unexpectedly get sick will also need to be treated. We should at least try this. ” 

 

And if such a rna drug against SARS-CoV-2 is found and works well, there is another advantage. In principle, it will paralyze all coronaviruses, including the sinister virus that would attempt to cause another pandemic.

Periode28-nov-2020

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