They find the ‘Achilles heel’ of SARS-CoV-2: is the door open to treatment for COVID-19?

Since the start of the COVID-19 pandemic, science has gone to great lengths to find a safe and effective antiviral treatment to fight SARS-CoV-2.

And while there has been unthinkable progress in vaccine development and experimental approaches are being actively applied in the reuse of licensed drugs for other purposes, the specific drug against this new virus has not yet been developed.

Until now?

According to a review Recently published, “certain regions of the SARS-CoV-2 genome could be a suitable target for future drugs”. This is what researchers at Goethe University, with its collaborators from the international COVID-19 -NMR consortium.

With the help of dedicated substance libraries, identified several small molecules that bind to certain areas of the SARS-CoV-2 genome and are almost never altered by mutations.

It is known that when SARS-CoV-2 infects a cell, it introduces its RNA and reprograms it so that the cell first produces viral proteins and then full viral particles. In search of effective molecules against SARS-CoV-2, researchers have so far mainly focused on viral proteins and how to block them, because this mechanism could prevent, or at least slow down, viral replication.

So far, most efforts have focused on proteins aimed at inhibiting viral spread, while few attempts to directly target the large viral RNA genome have been reported.

But apparently attacking the genome of the coronavirus, a long RNA molecule, could also stop or slow viral replication.

Scientists from the COVID-19-RMN consortium, coordinated by Professor Harald Schwalbe of the Goethe University Institute of Organic Chemistry and Chemical Biology, in Frankfurt, Germany, have taken an important first step in the development of a new class of anti-drug drugs. CoV-2 by identifying 15 short segments of the virus genome which are very similar in various coronaviruses and are known to perform essential regulatory functions.

On the other hand, they stressed that during the year 2020, these segments were rarely affected by mutations.

For the work, the researchers allowed a substance library of 768 chemically single small molecules to interact with the 15 RNA segments and analyzed the result using NMR spectroscopy. In NMR spectroscopy, molecules are first labeled with special types of atoms (stable isotopes) and then exposed to a strong magnetic field. Atomic nuclei are excited by a short radiofrequency pulse and emit a spectrum of frequencies, with the help of which it is possible to determine the structure of RNA and proteins and how and where small molecules bind.

This allowed the research team led by Professor Schwalbe to identify 69 small molecules that bound to 13 of the 15 RNA segments.

“Three of the molecules even bind specifically to a single segment of RNA. Thanks to this, we were able to demonstrate that the SARS-CoV-2 RNA is very suitable as a possible target drug structure – the researcher specified -. In view of the large number of SARS-CoV-2 mutations, these conservative RNA segments, such as those we have identified, are particularly interesting for developing potential inhibitors.. And since viral RNA makes up up to two-thirds of all RNA in an infected cell, we should be able to disrupt viral replication on a massive scale through the use of suitable molecules. “

“The results, as well as the methodological approach presented here, will affect the approaches of medical chemistry, but also the cellular targeting of the SARS-CoV-2 RNA”the researchers concluded with hope.

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