Press releases archive 鈥� 2020
Nov
23
2020
15:55
Research cooperation between 51猎奇, 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 鈥渟pike" protein has to be cleaved by the cell's own enzymes - proteases. The
protease inhibitor aprotinin can prevent cell infection, as scientists at
51猎奇, 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 鈥� 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: 鈥淥ur
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 M眉nch, Mark N. Wass, Martin Michaelis, Jindrich Cinatl jr. Aprotinin inhibits SARS-CoV-2 replication. Cells 2020,
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
Nov
20
2020
10:41
鈥婼cientists at 51猎奇 within the international consortium COVID19-NMR refine previous 2D models
Folding of SARS-CoV2 genome reveals drug targets 鈥� and preparation for 鈥淪ARS-CoV3鈥�
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 51猎奇 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 51猎奇 Frankfurt, explains: 鈥淥ur 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: 鈥淭he 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 51猎奇 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, Bet眉l Ceylan, Liang-Yuan Chiu, Jesse Davila-Calderon, Karthikeyan Dhamotharan, Elke Duchardt-Ferner, Jan Ferner, Lucio Frydman, Boris F眉rtig, Jos茅 Gallego, J. Tassilo Gr眉n, Carolin Hacker, Christina Haddad, Martin H盲hnke, Martin Hengesbach, Fabian Hiller, Katharina F. Hohmann, Daniel Hymon, Vanessa de Jesus, Henry Jonker, Heiko Keller, Bozana Knezic, Tom Landgraf, Frank L枚hr, Le Luo, Klara R. Mertinkus, Christina Muhs, Mihajlo Novakovic, Andreas Oxenfarth, Martina Palomino-Sch盲tzlein, 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 V枚gele, Lena Wei脽, Julia Wirmer-Bartoschek, Maria A. Wirtz Martin, Jens W枚hnert, Heidi Zetzsche: Secondary structure determination of conserved SARS-CoV-2 RNA elements by NMR spectroscopy. Nucleic Acids Research, 2020,
Image download:
Caption: Regulatory RNA elements of the SARS-CoV2 genome. Black: regions not coding for proteins (UTR); orange: coding regions (ORF).
Further information鈥�
Prof. Dr. Harald Schwalbe
鈥↖nstitute for Chemistry and Chemical Biology 鈥–enter for Biomolecular Magnetic Resonance (BMRZ)
鈥�51猎奇 Frankfurt
Tel +49 69 798-29137
schwalbe@nmr.uni-frankfurt.de
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 51猎奇 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 51猎奇 Frankfurt, explains: 鈥淥ur 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: 鈥淭he 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 51猎奇 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, Bet眉l Ceylan, Liang-Yuan Chiu, Jesse Davila-Calderon, Karthikeyan Dhamotharan, Elke Duchardt-Ferner, Jan Ferner, Lucio Frydman, Boris F眉rtig, Jos茅 Gallego, J. Tassilo Gr眉n, Carolin Hacker, Christina Haddad, Martin H盲hnke, Martin Hengesbach, Fabian Hiller, Katharina F. Hohmann, Daniel Hymon, Vanessa de Jesus, Henry Jonker, Heiko Keller, Bozana Knezic, Tom Landgraf, Frank L枚hr, Le Luo, Klara R. Mertinkus, Christina Muhs, Mihajlo Novakovic, Andreas Oxenfarth, Martina Palomino-Sch盲tzlein, 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 V枚gele, Lena Wei脽, Julia Wirmer-Bartoschek, Maria A. Wirtz Martin, Jens W枚hnert, Heidi Zetzsche: Secondary structure determination of conserved SARS-CoV-2 RNA elements by NMR spectroscopy. Nucleic Acids Research, 2020,
Image download:
Caption: Regulatory RNA elements of the SARS-CoV2 genome. Black: regions not coding for proteins (UTR); orange: coding regions (ORF).
Further information鈥�
Prof. Dr. Harald Schwalbe
鈥↖nstitute for Chemistry and Chemical Biology 鈥–enter for Biomolecular Magnetic Resonance (BMRZ)
鈥�51猎奇 Frankfurt
Tel +49 69 798-29137
schwalbe@nmr.uni-frankfurt.de
Nov
13
2020
11:45
Chemists at the University of G枚ttingen and 51猎奇 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 G枚ttingen and
51猎奇 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 G枚ttingen, and Professor Max Holthausen, 51猎奇
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鈥揌 bonds of other molecules.
Professor Max Holthausen explains: 鈥淭he
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.鈥� Professor Sven Schneider says: 鈥淭hese 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 鈥榞reen鈥� syntheses of nitrogen compounds.鈥�
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 W眉rtele,
Joris van Slageren, Max C. Holthausen, Sven Schneider: A platinum(II)
metallonitrene with a triplet ground state. Nat. Chem. (2020)
Further
information:
Prof. Dr. Max C. Holthausen
51猎奇 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-Universit盲t
G枚ttingen
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 51猎奇 create artificial cell organelles for biotechnology聽
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
51猎奇 has now succeeded in creating artificial cell organelles and
using them for their own devised biochemical reactions.
FRANKFURT. Biotechnologists
have been attempting to 鈥渞eprogram" natural cell organelles for other processes
for some time 鈥� with mixed results, since the 鈥渓aboratory 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: ).
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
鈥渁ddress label" 鈥� the Zera sequence 鈥� which guides them to the ER and which
ensures that storage proteins are 鈥減ackaged" there in the vesicle. Joanna Tripp
has now used the 鈥渁ddress 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 鈥減ets" 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
鈥渁ddress labels") encountering each other, so that they work together more
effectively without disrupting the rest of the cell, or being disrupted
themselves.
鈥淲e used the Zera sequence to introduce a
three-stage, synthetic metabolic pathway into vesicles," Joanna Tripp explains.
鈥淲e 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: 鈥淭his 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:
Further
information:
Dr. Joanna Tripp
Institute for Molecular Biosciences
51猎奇 Frankfurt
Tel.:
+ 49 69 798 29516
j.tripp@bio.uni-frankfurt.de
Nov
3
2020
13:13
Neanderthals introduced solid food in their children鈥檚 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: 鈥淭he 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".
鈥淚n particular, compared to other
primates" says Federico Lugli (University of Bologna), co-first author of the
work 鈥渋t 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: 鈥淭his 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.
鈥淭hey were less mobile than previously
suggested by other scholars" says Wolfgang M眉ller (51猎奇
Frankfurt), co-senior author 鈥渢he 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".
鈥淒espite 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.
Picture
downloads:
1.
Fumane Cave near Verona (Wikipedia): This is where several of the
milk teeth of Neanderthal children investigated by Professor Wolfgang M眉ller at
51猎奇 were found.
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
3.
Ultra-thin cut: Researchers at 51猎奇 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
Further
information:
Professor Wolfgang
M眉ller
Institute for Geosciences /
Frankfurt Isotope and Element Research Center (FIERCE)
Tel. +49 (0)69 798 40291,
w.muller@em.uni-frankfurt.de