Press releases – 2020

 

Nov 23 2020
15:55

Research cooperation between Goethe University, University of Kent and the Hannover Medical School

The drug aprotinin inhibits entry of SARS-CoV2 in host cells

In order for the SARS-CoV2 virus to enter host cells, its “spike" protein has to be cleaved by the cell's own enzymes - proteases. The protease inhibitor aprotinin can prevent cell infection, as scientists at Goethe University, the University of Kent and the Hannover Medical School have now discovered. An aprotinin aerosol is already approved in Russia for the treatment of influenza and could readily be tested for the treatment of COVID-19.

FRANKFURT. The surface of the SARS-CoV-2 virus is studded with spike proteins. The virus needs these in order to dock onto proteins (ACE2 receptors) on the surface of the host cell. Before this docking is possible, parts of the spike protein have to be cleaved by the host cell's enzymes – proteases.

In cell culture experiments with various cell types, the international scientific team led by Professor Jindrich Cinatl, Institute for Medical Virology at the University Hospital Frankfurt, Professor Martin Michaelis, and Dr Mark Wass (both University of Kent) demonstrated that the protease inhibitor aprotinin can inhibit virus replication by preventing SARS-CoV2 entry into host cells. Moreover, aprotinin appears to compensate for a SARS-CoV2-induced reduction of endogenous protease inhibitors in virus-infected cells.

Influenza viruses require host cell proteases for cell entry in a similar way as coronaviruses. Hence, an aprotinin aerosol is already approved in Russia for the treatment of influenza.

Professor Jindrich Cinatl said: “Our findings show that aprotinin is effective against SARS-CoV2 in concentrations that can be achieved in patients. In aprotinin we have a drug candidate for the treatment of COVID-19 that is already approved for other indications and could readily be tested in patients."

Publication: Denisa Bojkova, Marco Bechtel, Katie-May McLaughlin, Jake E. McGreig, Kevin Klann, Carla Bellinghausen, Gernot Rohde, Danny Jonigk, Peter Braubach, Sandra Ciesek, Christian Münch, Mark N. Wass, Martin Michaelis, Jindrich Cinatl jr. Aprotinin inhibits SARS-CoV-2 replication. Cells 2020, https://www.mdpi.com/2073-4409/9/11/2377

Further information:
Professor Dr. rer. nat. Jindrich Cinatl
Institute for Medical Virology
University Hospital Frankfurt am Main
Tel. +49 69 6301-6409
cinatl@em.uni-frankfurt.de
https://www.kgu.de/einrichtungen/institute/zentrum-der-hygiene/medizinische-virologie/forschung/research-group-cinatl/

 

Nov 20 2020
10:41

​Scientists at Goethe University within the international consortium COVID19-NMR refine previous 2D models

Folding of SARS-CoV2 genome reveals drug targets – and preparation for “SARS-CoV3”

For the first time, an international research alliance has observed the RNA folding structures of the SARS-CoV2 genome with which the virus controls the infection process. Since these structures are very similar among various beta corona viruses, the scientists not only laid the foundation for the targeted development of novel drugs for treating COVID-19, but also for future occurrences of infection with new corona viruses that may develop in the future.

FRANKFURT. The genetic code of the SARS-CoV2 virus is exactly 29,902 characters long, strung through a long RNA molecule. It contains the information for the production of 27 proteins. This is not much compared to the possible 40,000 kinds of protein that a human cell can produce. Viruses, however, use the metabolic processes of their host cells to multiply. Crucial to this strategy is that viruses can precisely control the synthesis of their own proteins.

SARS-CoV2 uses the spatial folding of its RNA hereditary molecule as control element for the production of proteins: predominantly in areas that do not code for the viral proteins, RNA single strands adopt structures with RNA double strand sections and loops. However, until now the only models of these foldings have been based on computer analyses and indirect experimental evidence.

Now, an international team of scientists led by chemists and biochemists at Goethe University and TU Darmstadt have experimentally tested the models for the first time. Researchers from the Israeli Weizmann Institute of Science, the Swedish Karolinska Institute and the Catholic University of Valencia were also involved.

The researchers were able to characterise the structure of a total of 15 of these regulatory elements. To do so, they used nuclear magnetic resonance (NMR) spectroscopy in which the atoms of the RNA are exposed to a strong magnetic field, and thereby reveal something about their spatial arrangement. They compared the findings from this method with the findings from a chemical process (dimethyl sulphate footprint) which allows RNA single strand regions to be distinguished from RNA double strand regions.

The coordinator of the consortium, Professor Harald Schwalbe from the Center for Biomolecular Magnetic Resonance at Goethe University Frankfurt, explains: “Our findings have laid a broad foundation for future understanding of how exactly SARS-CoV2 controls the infection process. Scientifically, this was a huge, very labour-intensive effort which we were only able to accomplish because of the extraordinary commitment of the teams here in Frankfurt and Darmstadt together with our partners in the COVID-19-NMR consortium. But the work goes on: together with our partners, we are currently investigating which viral proteins and which proteins of the human host cells interact with the folded regulatory regions of the RNA, and whether this may result in therapeutic approaches."

Worldwide, over 40 working groups with 200 scientists are conducting research within the COVID-19-NMR consortium, including 45 doctoral and postdoctoral students in Frankfurt working in two shifts per day, seven days of the week since the end of March 2020.

Schwalbe is convinced that the potential for discovery goes beyond new therapeutic options for infections with SARS-CoV2: “The control regions of viral RNA whose structure we examined are, for example, almost identical for SARS-CoV and also very similar for other beta-coronaviruses. For this reason, we hope that we can contribute to being better prepared for future 'SARS-CoV3' viruses."

The Center for Biomolecular Magnetic Resonance was founded in 2002 as research infrastructure at Goethe University Frankfurt and has since then received substantial funding from the State of Hessen.

Publication: Anna Wacker, Julia E. Weigand, Sabine R. Akabayov, Nadide Altincekic, Jasleen Kaur Bains, Elnaz Banijamali, Oliver Binas, Jesus Castillo-Martinez, Erhan Cetiner, Betül Ceylan, Liang-Yuan Chiu, Jesse Davila-Calderon, Karthikeyan Dhamotharan, Elke Duchardt-Ferner, Jan Ferner, Lucio Frydman, Boris Fürtig, José Gallego, J. Tassilo Grün, Carolin Hacker, Christina Haddad, Martin Hähnke, Martin Hengesbach, Fabian Hiller, Katharina F. Hohmann, Daniel Hymon, Vanessa de Jesus, Henry Jonker, Heiko Keller, Bozana Knezic, Tom Landgraf, Frank Löhr, Le Luo, Klara R. Mertinkus, Christina Muhs, Mihajlo Novakovic, Andreas Oxenfarth, Martina Palomino-Schätzlein, Katja Petzold, Stephen A. Peter, Dennis J. Pyper, Nusrat S. Qureshi, Magdalena Riad, Christian Richter, Krishna Saxena, Tatjana Schamber, Tali Scherf, Judith Schlagnitweit, Andreas Schlundt, Robbin Schnieders, Harald Schwalbe, Alvaro Simba-Lahuasi, Sridhar Sreeramulu, Elke Stirnal, Alexey Sudakov, Jan-Niklas Tants, Blanton S. Tolbert, Jennifer Vögele, Lena Weiß, Julia Wirmer-Bartoschek, Maria A. Wirtz Martin, Jens Wöhnert, Heidi Zetzsche: Secondary structure determination of conserved SARS-CoV-2 RNA elements by NMR spectroscopy. Nucleic Acids Research, 2020, https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkaa1013/5961789

Image download: http://www.uni-frankfurt.de/94413328

Caption: Regulatory RNA elements of the SARS-CoV2 genome. Black: regions not coding for proteins (UTR); orange: coding regions (ORF).

Further information

Prof. Dr. Harald Schwalbe

Institute for Chemistry and Chemical Biology 
Center for Biomolecular Magnetic Resonance (BMRZ)

Goethe University Frankfurt
Tel +49 69 798-29137
schwalbe@nmr.uni-frankfurt.de
http://schwalbe.org.chemie.uni-frankfurt.de/

 

Nov 13 2020
11:45

Chemists at the University of Göttingen and Goethe University Frankfurt characterise key compound for catalytic nitrogen atom transfer

Chemistry: How nitrogen is transferred by a catalyst

Catalysts with a metal-nitrogen bond can transfer nitrogen to organic molecules. In this process short-lived molecular species are formed, whose properties critically determine the course of the reaction and product formation. The key compound in a catalytic nitrogen-atom transfer reaction has now been analysed in detail by chemists at the University of Göttingen and Goethe University Frankfurt. The detailed understanding of this reaction will allow for the design of catalysts tailored for specific reactions.

FRANKFURT. The development of new drugs or innovative molecular materials with new properties requires specific modification of molecules. Selectivity control in these chemical transformations is one of the main goals of catalysis. This is particularly true for complex molecules with multiple reactive sites in order to avoid unnecessary waste for improved sustainability. The selective insertion of individual nitrogen atoms into carbon-hydrogen bonds of target molecules is, for instance, a particularly interesting goal of chemical synthesis. In the past, these kinds of nitrogen transfer reactions were postulated based on quantum-chemical computer simulations for molecular metal complexes with individual nitrogen atoms bound to the metal. These highly reactive intermediates have, however, previously escaped experimental observation. A closely entangled combination of experimental and theoretical studies is thus indispensable for detailed analysis of these metallonitrene key intermediates and, ultimately, the exploitation of catalytic nitrogen-atom transfer reactions.

Chemists in the groups of Professor Sven Schneider, University of Göttingen, and Professor Max Holthausen, Goethe University Frankfurt, in collaboration with the groups of Professor Joris van Slagern, University of Stuttgart and Professor Bas de Bruin, University of Amsterdam, have now been able for the first time to directly observe such a metallonitrene, measure it spectroscopically and provide a comprehensive quantum-chemical characterization. To this end, a platinum azide complex was transformed photochemically into a metallonitrene and examined both magnetometrically and using photo-crystallography. Together with theoretical modelling, the researchers have now provided a detailed report on a very reactive metallonitrene diradical with a single metal-nitrogen bond. The group was furthermore able to show how the unusual electronic structure of the platinum metallonitrene allows the targeted insertion of the nitrogen atom into, for example, C–H bonds of other molecules.

Professor Max Holthausen explains: “The findings of our work significantly extend the basic understanding of chemical bonding and reactivity of such metal complexes, providing the basis for a rational synthesis planning.” Professor Sven Schneider says: “These insertion reactions allow the use of metallonitrenes for the selective synthesis of organic nitrogen compounds through catalyst nitrogen atom transfer. This work therefore contributes to the development of novel ‘green’ syntheses of nitrogen compounds.”

The research was funded by the Deutsche Forschungsgemeinschaft and the European Research Council.

Publication: Jian Sun, Josh Abbenseth, Hendrik Verplancke, Martin Diefenbach, Bas de Bruin, David Hunger, Christian Würtele, Joris van Slageren, Max C. Holthausen, Sven Schneider: A platinum(II) metallonitrene with a triplet ground state. Nat. Chem. (2020) https://doi.org/10.1038/s41557-020-0522-4

Further information:
Prof. Dr. Max C. Holthausen
Goethe University Frankfurt am Main
Institute for Inorganic and Analytical Chemistry
Tel. +49 69 798 29430
max.holthausen@chemie.uni-frankfurt.de

Prof. Dr. Sven Schneider
Georg-August-Universität Göttingen
Institute for Inorganic Chemistry
Tel. +49 551 39 22829
sven.schneider@chemie.uni-goettingen.de

 

Nov 12 2020
13:53

Synthetic vesicles are mini-laboratories for customised molecules

Researchers at Goethe University create artificial cell organelles for biotechnology 

Cells of higher organisms use cell organelles to separate metabolic processes from each other. This is how cell respiration takes place in the mitochondria, the cell's power plants. They can be compared to sealed laboratory rooms in the large factory of the cell. A research team at Goethe University has now succeeded in creating artificial cell organelles and using them for their own devised biochemical reactions.

FRANKFURT. Biotechnologists have been attempting to “reprogram" natural cell organelles for other processes for some time – with mixed results, since the “laboratory equipment" is specialised on the function of organelles. Dr Joanna Tripp, early career researcher at the Institute for Molecular Biosciences has now developed a new method to produce artificial organelles in living yeast cells (ACS Synthetic Biology: https://doi.org/10.1021/acssynbio.0c00241).

To this end, she used the ramified system of tubes and bubbles in the endoplasmic reticulum (ER) that surrounds the nucleus.  Cells continually tie off bubbles, or vesicles, from this membrane system in order to transport substances to the cell membrane. In plants, these vesicles may also be used for the storage of proteins in seeds. These storage proteins are equipped with an “address label" – the Zera sequence – which guides them to the ER and which ensures that storage proteins are “packaged" there in the vesicle. Joanna Tripp has now used the “address label" Zera to produce targeted vesicles in yeast cells and introduce several enzymes of a biochemical metabolic pathway.

This represents a milestone from a biotechnical perspective. Yeast cells, the “pets" of synthetic biology not only produce numerous useful natural substances, but can also be genetically changed to produce industrially interesting molecules on a grand scale, such as biofuels or anti-malaria medicine.

In addition to the desired products, however, undesirable by-products or toxic intermediates often occur as well. Furthermore, the product can be lost due to leaks in the cell, or reactions can be too slow. Synthetic cell organelles offer remedies, with only the desired enzymes (with “address labels") encountering each other, so that they work together more effectively without disrupting the rest of the cell, or being disrupted themselves.

“We used the Zera sequence to introduce a three-stage, synthetic metabolic pathway into vesicles," Joanna Tripp explains. “We have thus created a reaction space containing exactly what we want. We were able to demonstrate that the metabolic pathway in the vesicles functions in isolation to the rest of the cell."

The biotechnologist selected an industrially relevant molecule for this process: muconic acid, which is further processed industrially to adipic acid. This is an intermediate for nylon and other synthetic materials. Muconic acid is currently won from raw oil. A future large-scale production using yeast cells would be significantly more environment-friendly and sustainable. Although a portion of the intermediate protocatechuic acid is lost because the vesicle membrane is porous, Joanna Tripp views this as a solvable problem.

Professor Eckhard Boles, Head of the Department of Physiology and Genetics of Lower Eukaryotes observes: “This is a revolutionary new method of synthetic biology. With the novel artificial organelles, we now have the option of generating various processes in the cell anew, or to optimise them." The method is not limited to yeast cells, but can be utilised for eukaryotic cells in general. It can also be applied to other issues, e.g. for reactions that have previously not been able to take place in living cells because they may require enzymes that would disrupt the cell metabolic process.

Publication: Mara Reifenrath, Mislav Oreb, Eckhard Boles, Joanna Tripp: Artificial ER-Derived Vesicles as Synthetic Organelles for in Vivo Compartmentalization of Biochemical Pathways, in:
ACS Synthetic Biology: https://doi.org/10.1021/acssynbio.0c00241

Further information:
Dr. Joanna Tripp
Institute for Molecular Biosciences
Goethe University Frankfurt
Tel.: + 49 69 798 29516 
j.tripp@bio.uni-frankfurt.de

 

Nov 3 2020
13:13

Neanderthals introduced solid food in their children’s diet at around 5-6 months of age

Just like us - Neanderthal children grew and were weaned similar to us

Neanderthals behaved not so differently from us in raising their children, whose pace of growth was similar to Homo sapiens. Thanks to the combination of geochemical and histological analyses of three Neanderthal milk teeth, researchers were able to determine their pace of growth and the weaning onset time. These teeth belonged to three different Neanderthal children who have lived between 70,000 and 45,000 years ago in a small area of northeastern Italy.

FRANKFURT/KENT/BOLOGNA/FERRARA. Teeth grow and register information in form of growth lines, akin to tree rings, that can be read through histological techniques. Combining such information with chemical data obtained with a laser-mass spectrometer, in particular strontium concentrations, the scientists were able to show that these Neanderthals introduced solid food in their children's diet at around 5-6 months of age.

Not cultural but physiological

Alessia Nava (University of Kent, UK), co-first author of the work, says: “The beginning of weaning relates to physiology rather than to cultural factors. In modern humans, in fact, the first introduction of solid food occurs at around 6 months of age when the child needs a more energetic food supply, and it is shared by very different cultures and societies. Now, we know that also Neanderthals started to wean their children when modern humans do".

“In particular, compared to other primates" says Federico Lugli (University of Bologna), co-first author of the work “it is highly conceivable that the high energy demand of the growing human brain triggers the early introduction of solid foods in child diet".

Neanderthals are our closest cousins within the human evolutionary tree. However, their pace of growth and early life metabolic constraints are still highly debated within the scientific literature.

Stefano Benazzi (University of Bologna), co-senior author, says: “This work's results imply similar energy demands during early infancy and a close pace of growth between Homo sapiens and Neanderthals. Taken together, these factors possibly suggest that Neanderthal newborns were of similar weight to modern human neonates, pointing to a likely similar gestational history and early-life ontogeny, and potentially shorter inter-birth interval".

Home, sweet home

Other than their early diet and growth, scientists also collected data on the regional mobility of these Neanderthals using time-resolved strontium isotope analyses.

“They were less mobile than previously suggested by other scholars" says Wolfgang Müller (Goethe University Frankfurt), co-senior author “the strontium isotope signature registered in their teeth indicates in fact that they have spent most of the time close to their home: this reflects a very modern mental template and a likely thoughtful use of local resources".

“Despite the general cooling during the period of interest, Northeastern Italy has almost always been a place rich in food, ecological variability and caves, ultimately explaining survival of Neanderthals in this region till about 45,000 years ago" says Marco Peresani (University of Ferrara), co-senior author and responsible for findings from archaeological excavations at sites of De Nadale and Fumane.

This research adds a new piece in the puzzling pictures of Neanderthal, a human species so close to us but still so enigmatic. Specifically, researchers exclude that the Neanderthal small population size, derived in earlier genetic analyses, was driven by differences in weaning age, and that other biocultural factors led to their demise. This will be further investigated within the framework of the ERC project SUCCESS ('The Earliest Migration of Homo sapiens in Southern Europe - Understanding the biocultural processes that define our uniqueness'), led by Stefano Benazzi at University of Bologna.

Publication: Alessia Nava, Federico Lugli, Matteo Romandini, Federica Badino, David Evans, Angela H. Helbling, Gregorio Oxilia, Simona Arrighi, Eugenio Bortolini, Davide Delpiano, Rossella Duches, Carla Figus, Alessandra Livraghi, Giulia Marciani, Sara Silvestrini, Anna Cipriani, Tommaso Giovanardi, Roberta Pini, Claudio Tuniz, Federico Bernardini, Irene Dori, Alfredo Coppa, Emanuela Cristiani, Christopher Dean, Luca Bondioli, Marco Peresani, Wolfgang Müller, Stefano Benazzi, Early life of Neanderthals. Proceedings of the National Academy of Sciences Oct 2020, DOI: 10.1073/pnas.2011765117


Picture downloads:

1. Fumane Cave near Verona (Wikipedia): This is where several of the milk teeth of Neanderthal children investigated by Professor Wolfgang Müller at Goethe University were found. https://de.wikipedia.org/wiki/Grotta_di_Fumane#/media/Datei:Grotta_di_Fumane_3.jpg

2. Neanderthal milk teeth: Presumably a Neanderthal child lost this tooth 40,000 to 70,000 year ago when his or her permanent teeth came in. Credit: ERC project SUCCESS, University of Bologna, Italy
http://www.uni-frankfurt.de/93639226

3. Ultra-thin cut: Researchers at Goethe University cut paper-thin slices off of a Neanderthal milk tooth. The teeth are subsequently put back together and reconstructed. Credit/video still: Luca Bondioli and Alessia Nava, Rome, Italy
http://www.uni-frankfurt.de/93639334

Further information:

Professor Wolfgang Müller
Institute for Geosciences /
Frankfurt Isotope and Element Research Center (FIERCE)
Tel. +49 (0)69 798 40291,
w.muller@em.uni-frankfurt.de
http://www.uni-frankfurt.de/49540288/Homepage-Mueller