FRANKFURT. A team of biochemists and virologists at
Goethe University and the Frankfurt University Hospital were able to observe how
human cells change upon infection with SARS-CoV-2, the virus causing COVID-19
in people. The scientists tested a series of compounds in laboratory models and
found some which slowed down or stopped virus reproduction. These results now
enable the search for an active substance to be narrowed down to a small number
of already approved drugs. (Nature DOI: 10.1038/s41586-020-2332-7).
Based on these findings, a US company reports that it is preparing clinical
trials. A Canadian company is also starting a clinical study
with a different substance.
Since the start
of February, the Medical Virology of the Frankfurt University Hospital has been
in possession of a SARS-CoV-2
infection cell culture system. The
Frankfurt scientists in Professor Sandra Ciesek's team succeeded in cultivating
the virus in colon cells from swabs taken from two infected individuals
returning from Wuhan (Hoehl et al. NEJM 2020).
Using a technique developed at the
Institute for Biochemistry II at Goethe University Frankfurt, researchers from
both institutions were together able to show how a SARS-CoV-2 infection changes
the human host cells. The scientists used a particular form of mass
spectrometry called the mePROD method, which they had developed only a few
months previously. This method makes it possible to determine the amount and
synthesis rate of thousands of proteins within a cell.
The findings paint a picture of the
progression of a SARS-CoV-2 infection: whilst many viruses shut down the host's
protein production to the benefit of viral proteins, SARS-CoV-2 only slightly
influences the protein production of the host cell, with the viral proteins
appearing to be produced in competition to host cell proteins. Instead, a SARS-CoV-2
infection leads to an increased protein synthesis machinery in the cell. The researchers
suspected this was a weak spot of the virus and were indeed able to
significantly reduce virus reproduction using something known as translation
inhibitors, which shut down protein production.
Twenty-four hours after infection, the
virus causes distinct changes to the composition of the host proteome: while
cholesterol metabolism is reduced, activities in carbohydrate metabolism and in
modification of RNA as protein precursors increase. In line with this, the
scientists were successful in stopping virus reproduction in cultivated cells by
applying inhibitors of these processes. Similar success was achieved by using a
substance that inhibits the production of building blocks for the viral genome.
The findings have already created a stir on
the other side of the Atlantic: in keeping with common practise since the
beginning of the corona crisis, the Frankfurt researchers made these findings
immediately available on a preprint server and on the website of the Institute
for Biochemistry II (http://pqc.biochem2.de#coronavirus). Professor Ivan Dikic, Director of the
Institute, comments: “Both the culture of 'open science', in which we share our
scientific findings as quickly as possible, and the interdisciplinary collaboration
between biochemists and virologists contributed to this success. This project started
not even three months ago, and has already revealed new therapeutic approaches
Professor Sandra Ciesek, Director of the
Institute for Medical Virology at the University Hospital Frankfurt, explains:
“In a unique situation like this we also have to take new paths in research. An
already existing cooperation between the Cinatl and Münch laboratories made it
possible to quickly focus the research on SARS-CoV-2. The findings so far are a
wonderful affirmation of this approach of cross-disciplinary collaborations."
Among the substances that stopped viral
reproduction in the cell culture system was 2-Deoxy-D-Glucose (2-DG), which interferes
directly with the carbohydrate metabolism necessary for viral reproduction. The
US company Moleculin Biotech possesses a substance called WP1122, a prodrug
similar to 2-DG. Recently, Moleculin Biotech announced that they are preparing
a clinical trial with this substance based on the results from Frankfurt. https://www.moleculin.com/covid-19/.
Based on another one of the substances
tested in Frankfurt, Ribavirin, the Canadian company Bausch Health Americas is
starting a clinical study with 50 participants: https://clinicaltrials.gov/ct2/show/NCT04356677?term=04356677&draw=2&rank=1
Dr Christian Münch, Head of the Protein
Quality Control Group at the Institute for Biochemistry II and lead author, comments:
“Thanks to the mePROD-technology we developed, we were for the first time able
to trace the cellular changes upon infection over time and with high detail in
our laboratory. We were obviously aware of the potential scope of our findings.
However, they are based on a cell culture system and require further testing. The
fact that our findings may now immediately trigger further in vivo
studies with the purpose of drug development is definitely a great stroke of
luck." Beyond this, there are also other potentially interesting candidates
among the inhibitors tested, says Münch, some of which have already been
approved for other indications.
Professor Jindrich Cinatl from the
Institute of Medical Virology and lead author explains: “The successful use of
substances that are components of already approved drugs to combat SARS-CoV-2 is
a great opportunity in the fight against the virus. These substances are
already well characterised, and we know how they are tolerated by patients.
This is why there is currently a global search for these types of substances.
In the race against time, our work can now make an important contribution as to
which directions promise the fastest success."
SARS-CoV-2 infected host cell proteomics
reveal potential therapy targets. Denisa Bojkova, Kevin Klann, Benjamin Koch,
Marek Widera, David Krause, Sandra Ciesek, Jindrich Cinatl, Christian Münch. Nature DOI: 10.1038/s41586-020-2332-7,
https://www.nature.com/articles/s41586-020-2332-7 (active starting 10am London time (BST), 5am US Eastern Time)
downloaded here: http://www.uni-frankfurt.de/88340061
Dr. Christian Münch (Credit: Uwe Dettmar
for Goethe University Frankfurt)
Prof. Dr. rer. nat. Jindrich Cinatl (Credit:
University Hospital Frankfurt)
about the mePROD method: Biochemistry researchers at Goethe
University develop a new proteomics procedure https://aktuelles.uni-frankfurt.de/englisch/biochemistry-researchers-at-goethe-university-develop-new-protoeomics-procedure/
Professor Dr. rer. nat. Jindrich Cinatl, Head of the Research Group Cinatl, Institute for Medical Virology, University Hospital Frankfurt am Main, Tel.
+49 69 6301-6409, E-mail: firstname.lastname@example.org,
Christian Münch, Head of the Group Protein Quality Control, Institute for Biochemistry II, Goethe University Frankfurt am Main Tel: +49 69 6301 6599, E-Mail: email@example.com,