Achilles whole or viral RNA

When SARS-CoV-2 infects a cell, it introduces its RNA and reprograms it so that the cell first produces viral proteins and then whole viral particles. In the search for active substances against SARS-CoV-2, researchers so far have mainly focused on viral proteins and their blocking, as this promises to prevent, or at least slow down, replication. But attacking the viral genome, a long RNA molecule, could also stop or slow down viral replication.

Scientists in the COVID-19-NMR consortium, coordinated by Professor Harald Schwalbe of the Institute of Organic Chemistry and Chemical Biology at Goethe University, have now taken an important first step in the development of such a new class of SARS-CoV. -2 drugs. They identified 15 short segments of the SARS-CoV-2 genome that are very similar in various coronaviruses and are known to perform essential regulatory functions. Also during 2020, these segments were very rarely affected by mutations.

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 means of a short radiofrequency pulse and emit a frequency spectrum, with the help of which it is possible to determine the structure of RNA and proteins and how and where small molecules bind together.

This allowed the research team led by Professor Schwalbe to identify 69 small molecules that bound to 13 of the 15 RNA segments. Professor Harald Schwalbe states that “three of the molecules even bind specifically to a single segment of RNA. Thanks to this, we were able to show that SARS-CoV-2 RNA is perfectly suited as a potential target structure for drugs. large number of mutations in SARS-CoV-2, such conservative RNA segments, like those we have identified, are particularly interesting for developing potential inhibitors.And since viral RNA represents up to two-thirds of all ‘RNA in an infected cell, we should be able to disrupt viral replication on a massive scale using suitable molecules. In this context, continues Schwalbe, researchers have already started follow-up trials with readily available substances that are chemically similar to the binding partners of the substance library.