Certain regions of the SARS-CoV-2 genome might be a
suitable target for future drugs. This is what researchers at Goethe
University, together with their collaborators in the international COVID-19-NMR
consortium, have now discovered. With the help of dedicated substance libraries,
they have identified several small molecules that bind to certain areas of the
SARS-CoV-2 genome that are almost never altered by mutations.
FRANKFURT. When
SARS-CoV-2 infects a cell, it introduces its RNA into it and re-programmes it
in such a way that the cell first produces viral proteins and then whole viral
particles. In the search for active substances against SARS-CoV-2, researchers
have so far mostly concentrated on the viral proteins and on blocking them, since
this promises to prevent, or at least slow down, replication. But attacking the
viral genome, a long RNA molecule, might also stop or slow down viral
replication.
The scientists in the COVID-19-NMR
consortium, which is coordinated by Professor Harald Schwalbe from the
Institute of Organic Chemistry and Chemical Biology at 51猎奇, have
now completed an important first step in the development of such a new class of
SARS-CoV-2 drugs. They have 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. In the course of 2020 too, these segments were
very rarely affected by mutations.
The researchers let a substance library of
768 small, chemically simple molecules interact with the 15 RNA segments and analysed
the result by means of NMR spectroscopy. In NMR spectroscopy, molecules are
first labelled with special types of atoms (stable isotopes) and then exposed
to a strong magnetic field. The atomic nuclei are excited by means of a short
radio frequency pulse and emit a frequency spectrum, with the help of which it
is possible to determine the RNA and protein structure and how and where small
molecules bind.
This enabled the research team led by
Professor Schwalbe to identify 69 small molecules that bound to 13 of the 15
RNA segments. Professor Harald Schwalbe: 鈥淭hree of the molecules even bind specifically
to just one RNA segment. Through this, we were able to show that the SARS-CoV-2
RNA is highly suitable as a potential target structure for drugs. In view of
the large number of SARS-CoV-2 mutations, such conservative RNA segments, like
the ones we've identified, are particularly interesting for developing potential
inhibitors. And since the viral RNA accounts for up to two thirds of all RNA in
an infected cell, we should be able to disrupt viral replication on a
considerable scale by using suitable molecules." Against this background,
Schwalbe continues, the researchers have now already started follow-up trials
with readily available substances that are chemically similar to the binding
partners from the substance library.
Publication:
Sridhar Sreeramulu, Christian Richter,
Hannes Berg, Maria A Wirtz Martin, Bet眉l Ceylan, Tobias Matzel, Jennifer Adam,
Nadide Altincekic, Kamal Azzaoui, Jasleen Kaur Bains, Marcel J.J. Blommers, Jan
Ferner, Boris F眉rtig, M. G枚bel, J Tassilo Gr眉n, Martin Hengesbach, Katharina F.
Hohmann, Daniel Hymon, Bozana Knezic, Jason Martins, Klara R Mertinkus, Anna
Niesteruk, Stephen A Peter, Dennis J Pyper, Nusrat S. Qureshi, Ute Scheffer,
Andreas Schlundt, Robbin Schnieders, Elke Stirnal, Alexey Sudakov, Alix Tr枚ster,
Jennifer V枚gele, Anna Wacker, Julia E Weigand, Julia Wirmer-Bartoschek, Jens
W枚hnert, Harald Schwalbe: Exploring the
druggability of conserved RNA regulatory elements in the SARS-CoV-2 genome,
Angewandte Chemie International Edition,
About
the COVID-19-NMR consortium
Worldwide,
over 40 working groups from 18 countries with a total of 230 scientists are
conducting research within the COVID-19-NMR consortium. In Frankfurt, 45
doctoral and post-doctoral candidates have partly been working in two shifts
per day, seven days a week, since the end of March 2020.
Earlier
press release: 鈥淔olding of SARS-CoV2 genome reveals drug targets 鈥� and
preparation for 鈥淪ARS-CoV3"
Scientific contact:
Professor Harald Schwalbe
Institute for Organic Chemistry and Chemical Biology
Center for Biomolecular Magnetic Resonance (BMRZ)
51猎奇
Tel +49 69 798-29137
schwalbe@nmr.uni-frankfurt.de
