Press releases archive 鈥� 2020
Jul
29
2020
12:45
Frankfurt scientists identify possible Achilles鈥� heel of SARS-CoV-2 virus
COVID-19 research: Anti-viral strategy with double effect
FRANKFURT. When the SARS-CoV-2 virus penetrates human cells, it lets the human host cell produce proteins for it. One of these viral proteins, called PLpro, is essential for the replication and rapid spread of the virus. An international team of researchers led by 51猎奇 and University Hospital Frankfurt has now discovered that the pharmacological inhibition of this viral enzyme not only blocks virus replication but also strengthens the anti-viral immune response at the same time (Nature, DOI 10.1038/s41586-020-2601-5).
In the case of an infection, the SARS-CoV-2 virus must overcome various defense mechanisms of the human body, including its non-specific or innate immune defense. During this process, infected body cells release messenger substances known as type 1 interferons. These attract natural killer cells, which kill the infected cells.
One of the reasons the SARS-CoV-2 virus is so successful 鈥� and thus dangerous 鈥� is that it can suppress the non-specific immune response. In addition, it lets the human cell produce the viral protein PLpro (papain-like protease). PLpro has two functions: It plays a role in the maturation and release of new viral particles, and it suppresses the development of type 1 interferons. The German and Dutch researchers have now been able to monitor these processes in cell culture experiments. Moreover, if they blocked PLpro, virus production was inhibited and the innate immune response of the human cells was strengthened at the same time.
Professor Ivan 膼iki膰, Director of the Institute of Biochemistry II at University Hospital Frankfurt and last author of the paper, explains: 鈥淲e used the compound GRL-0617, a non-covalent inhibitor of PLpro, and examined its mode of action very closely in terms of biochemistry, structure and function. We concluded that inhibiting PLpro is a very promising double-hit therapeutic strategy against COVID-19. The further development of PLpro-inhibiting substance classes for use in clinical trials is now a key challenge for this therapeutic approach."
Another important finding from this work is that the viral protein PLpro of SARS-CoV-2 cleaves off ISG-15 (interferon-stimulated gene 15) from cellular proteins with a higher level of activity than the SARS equivalent, which leads to greater inhibition of type I interferon production. This is concordant with recent clinical observations which show that COVID-19 exhibits a reduced interferon response in comparison to other respiratory viruses such as influenza and SARS.
To understand in detail how inhibiting PLpro stops the virus, researchers in Frankfurt, Munich, Mainz, Freiburg and Leiden have worked closely together and pooled their biochemical, structural, IT and virological expertise.
Donghyuk Shin, postdoctoral researcher and first author of the paper, says: 鈥淧ersonally, I would like to underline the significance of science and research and in particular emphasize the potential generated by a culture of collaboration. When I saw our joint results, I was immensely grateful for being a researcher."
Professor Sandra Ciesek, Director of the Institute of Medical Virology at University Hospital Frankfurt, explains that the papain-like protease is an extremely attractive anti-viral goal for her as a physician because its inhibition would be a 鈥渄ouble strike" against SARS-CoV-2. She highlights the excellent collaboration between the two institutes: 鈥淓specially when investigating a new clinical picture, everyone profits from interdisciplinary collaboration as well as different experiences and viewpoints."
Publication: Donghyuk Shin, Rukmini Mukherjee, Diana Grewe, Denisa Bojkova, Kheewoong Baek, Anshu Bhattacharya, Laura Schulz, Marek Widera, Ahmad Reza Mehdipour, Georg Tascher, Klaus-Peter Knobeloch, Krishnaraj Rajalingam, Huib Ovaa, Brenda Schulman, Jindrich Cinatl, Gerhard Hummer, Sandra Ciesek, Ivan Dikic. Inhibition of papain-like protease PLpro blocks 1 SARS-CoV-2 spread and 2 promotes anti-viral immunity. Nature, DOI 10.1038/s41586-020-2601-5,
Further information:
Professor Ivan 膼iki膰
Director of the Institute of Biochemistry II of University Hospital Frankfurt
Group Leader at the Buchmann Institute for Molecular Life Sciences, 51猎奇 Frankfurt
Max Planck Fellow at Max Planck Institute of Biophysics, Frankfurt
Tel.: +49 (0)69 6301-5964, email: dikic@biochem2.uni-frankfurt.de, Twitter: @iDikic2
In the case of an infection, the SARS-CoV-2 virus must overcome various defense mechanisms of the human body, including its non-specific or innate immune defense. During this process, infected body cells release messenger substances known as type 1 interferons. These attract natural killer cells, which kill the infected cells.
One of the reasons the SARS-CoV-2 virus is so successful 鈥� and thus dangerous 鈥� is that it can suppress the non-specific immune response. In addition, it lets the human cell produce the viral protein PLpro (papain-like protease). PLpro has two functions: It plays a role in the maturation and release of new viral particles, and it suppresses the development of type 1 interferons. The German and Dutch researchers have now been able to monitor these processes in cell culture experiments. Moreover, if they blocked PLpro, virus production was inhibited and the innate immune response of the human cells was strengthened at the same time.
Professor Ivan 膼iki膰, Director of the Institute of Biochemistry II at University Hospital Frankfurt and last author of the paper, explains: 鈥淲e used the compound GRL-0617, a non-covalent inhibitor of PLpro, and examined its mode of action very closely in terms of biochemistry, structure and function. We concluded that inhibiting PLpro is a very promising double-hit therapeutic strategy against COVID-19. The further development of PLpro-inhibiting substance classes for use in clinical trials is now a key challenge for this therapeutic approach."
Another important finding from this work is that the viral protein PLpro of SARS-CoV-2 cleaves off ISG-15 (interferon-stimulated gene 15) from cellular proteins with a higher level of activity than the SARS equivalent, which leads to greater inhibition of type I interferon production. This is concordant with recent clinical observations which show that COVID-19 exhibits a reduced interferon response in comparison to other respiratory viruses such as influenza and SARS.
To understand in detail how inhibiting PLpro stops the virus, researchers in Frankfurt, Munich, Mainz, Freiburg and Leiden have worked closely together and pooled their biochemical, structural, IT and virological expertise.
Donghyuk Shin, postdoctoral researcher and first author of the paper, says: 鈥淧ersonally, I would like to underline the significance of science and research and in particular emphasize the potential generated by a culture of collaboration. When I saw our joint results, I was immensely grateful for being a researcher."
Professor Sandra Ciesek, Director of the Institute of Medical Virology at University Hospital Frankfurt, explains that the papain-like protease is an extremely attractive anti-viral goal for her as a physician because its inhibition would be a 鈥渄ouble strike" against SARS-CoV-2. She highlights the excellent collaboration between the two institutes: 鈥淓specially when investigating a new clinical picture, everyone profits from interdisciplinary collaboration as well as different experiences and viewpoints."
Publication: Donghyuk Shin, Rukmini Mukherjee, Diana Grewe, Denisa Bojkova, Kheewoong Baek, Anshu Bhattacharya, Laura Schulz, Marek Widera, Ahmad Reza Mehdipour, Georg Tascher, Klaus-Peter Knobeloch, Krishnaraj Rajalingam, Huib Ovaa, Brenda Schulman, Jindrich Cinatl, Gerhard Hummer, Sandra Ciesek, Ivan Dikic. Inhibition of papain-like protease PLpro blocks 1 SARS-CoV-2 spread and 2 promotes anti-viral immunity. Nature, DOI 10.1038/s41586-020-2601-5,
Further information:
Professor Ivan 膼iki膰
Director of the Institute of Biochemistry II of University Hospital Frankfurt
Group Leader at the Buchmann Institute for Molecular Life Sciences, 51猎奇 Frankfurt
Max Planck Fellow at Max Planck Institute of Biophysics, Frankfurt
Tel.: +49 (0)69 6301-5964, email: dikic@biochem2.uni-frankfurt.de, Twitter: @iDikic2
Jul
23
2020
08:51
鈥婫eoscientists from 51猎奇 create sedimentary archive with annual resolution
2,000 years of storms in the Caribbean
FRANKFURT. The hurricanes in the Caribbean became more frequent and their force varied noticeably around the same time that classical Mayan culture in Central America suffered its final demise: We can gain these and other insights by looking at the climate archive created under the leadership of geoscientists from 51猎奇 and now presented in an article in 鈥淣ature" journal's 鈥淪cientific Reports" on 16 July.
Tropical cyclones in the Atlantic (hurricanes) are a substantial threat for the lives and property of the local population in the Caribbean and neighboring regions, such as the south-east of the USA. The storms' increasing force, described in Chapter 15 of the report by the Intergovernmental Panel on Climate Change (IPCC Report), raises the probability of ecological and social catastrophes, as the occurrence of such cyclones over the past 20 years, which caused devastating damage, has shown. The climate models used to date, which could help to estimate the danger better, are, however, based on data that are lacking in spatial and temporal depth. Instrumental climate data, such as regular measurement of sea surface temperatures and reliable chronicling of hurricanes, date back only to the 19th century, at most.
In the framework of a research project (Gi 222/31) funded by the German Research Foundation, the Biosedimentology Working Group at the Department of Geosciences of the Faculty of Geosciences and Geography (Professor Eberhard Gischler) of 51猎奇 has now been able to build up and analyze a sedimentary 鈥渟torm archive" that covers almost the entire Common Era (2,000 years) with annual resolution. The archive comprises fine-grained annual layers of sediments from the 125-meter-deep bottom of the Blue Hole, a flooded karst sinkhole on the Lighthouse Reef Atoll off the coast of Belize (Central America). There, 2.5 mm of lime mud, composed of shell debris from organisms in the reef lagoon along with changing amounts of organic matter, collect year after year. Coarser layers up to several centimeters thick that constitute tempestites (storm sediments) are intercalated in these fine-grained sediments. They mostly consist of shell debris from reef organisms living on the edge of the atoll. The almost 9-metre-long drill core from the bottom of the Blue Hole, which was recovered with the help of an electrical vibracorer, spans the last 1,885 years with a total of 157 storm layers.
In the framework of extensive studies conducted by doctoral researcher Dominik Schmitt and collaboration between the Biosedimentology Working Group and colleagues at the University of Bern (Switzerland), it has become apparent that both short-term and long-term climate phenomena, such as the El Ni帽o Southern Oscillation (ENSO), the North Atlantic Oscillation (NAO) and the Atlantic Multidecadal Oscillation (AMO), have influenced storm activity over the last 2,000 years and are mirrored in the new climate archive. The beginning of the Medieval Warm Period (approx. AD 900-1100) constitutes an important transition period when the activity of tropical cyclones changed substantially, presumably in conjunction with the shift of the Intertropical Convergence Zone (the low-pressure zone where northern and southern trade winds converge) towards the south: From AD 100-900, storm activity in the region tended to be more stable and weaker, while since AD 900 up until today it has been more variable and more vigorous. Interestingly, this change in the increase of cyclone frequency goes hand in hand with the occurrence of a few, very thick, coarse-grained storm layers and coincides with the final demise of the classical Mayan culture in Central America. It is possible that the increased impact of hurricanes on the Central American mainland, combined with extensive flooding of cultivated land in the Mayan lowlands and rainfall-induced erosion in the backlands of the Mayan Mountains of Belize 鈥� apart from the recurring periods of drought already known 鈥� was another environmental factor that influenced the end of the Maya's high culture.
Publication:
Images are available for download under the following link:
Captions:
Picture 1: Aerial photograph of the Blue Hole, a flooded karst sinkhole on Lighthouse Reef, Belize, where the research team from Frankfurt was able to tap into 2,000-year-old sediment layers. (Photo: Gischler)
Picture 2: This drill core section from the Blue Hole shows the annual layering (green-beige) and storm events (light-colored). (Photo: Schmitt)
Further information: Professor Eberhard Gischler, Department of Geosciences, Riedberg Campus, Tel.: +49(0)69-798 40183, email: gischler@em.uni-frankfurt.de
Tropical cyclones in the Atlantic (hurricanes) are a substantial threat for the lives and property of the local population in the Caribbean and neighboring regions, such as the south-east of the USA. The storms' increasing force, described in Chapter 15 of the report by the Intergovernmental Panel on Climate Change (IPCC Report), raises the probability of ecological and social catastrophes, as the occurrence of such cyclones over the past 20 years, which caused devastating damage, has shown. The climate models used to date, which could help to estimate the danger better, are, however, based on data that are lacking in spatial and temporal depth. Instrumental climate data, such as regular measurement of sea surface temperatures and reliable chronicling of hurricanes, date back only to the 19th century, at most.
In the framework of a research project (Gi 222/31) funded by the German Research Foundation, the Biosedimentology Working Group at the Department of Geosciences of the Faculty of Geosciences and Geography (Professor Eberhard Gischler) of 51猎奇 has now been able to build up and analyze a sedimentary 鈥渟torm archive" that covers almost the entire Common Era (2,000 years) with annual resolution. The archive comprises fine-grained annual layers of sediments from the 125-meter-deep bottom of the Blue Hole, a flooded karst sinkhole on the Lighthouse Reef Atoll off the coast of Belize (Central America). There, 2.5 mm of lime mud, composed of shell debris from organisms in the reef lagoon along with changing amounts of organic matter, collect year after year. Coarser layers up to several centimeters thick that constitute tempestites (storm sediments) are intercalated in these fine-grained sediments. They mostly consist of shell debris from reef organisms living on the edge of the atoll. The almost 9-metre-long drill core from the bottom of the Blue Hole, which was recovered with the help of an electrical vibracorer, spans the last 1,885 years with a total of 157 storm layers.
In the framework of extensive studies conducted by doctoral researcher Dominik Schmitt and collaboration between the Biosedimentology Working Group and colleagues at the University of Bern (Switzerland), it has become apparent that both short-term and long-term climate phenomena, such as the El Ni帽o Southern Oscillation (ENSO), the North Atlantic Oscillation (NAO) and the Atlantic Multidecadal Oscillation (AMO), have influenced storm activity over the last 2,000 years and are mirrored in the new climate archive. The beginning of the Medieval Warm Period (approx. AD 900-1100) constitutes an important transition period when the activity of tropical cyclones changed substantially, presumably in conjunction with the shift of the Intertropical Convergence Zone (the low-pressure zone where northern and southern trade winds converge) towards the south: From AD 100-900, storm activity in the region tended to be more stable and weaker, while since AD 900 up until today it has been more variable and more vigorous. Interestingly, this change in the increase of cyclone frequency goes hand in hand with the occurrence of a few, very thick, coarse-grained storm layers and coincides with the final demise of the classical Mayan culture in Central America. It is possible that the increased impact of hurricanes on the Central American mainland, combined with extensive flooding of cultivated land in the Mayan lowlands and rainfall-induced erosion in the backlands of the Mayan Mountains of Belize 鈥� apart from the recurring periods of drought already known 鈥� was another environmental factor that influenced the end of the Maya's high culture.
Publication:
Images are available for download under the following link:
Captions:
Picture 1: Aerial photograph of the Blue Hole, a flooded karst sinkhole on Lighthouse Reef, Belize, where the research team from Frankfurt was able to tap into 2,000-year-old sediment layers. (Photo: Gischler)
Picture 2: This drill core section from the Blue Hole shows the annual layering (green-beige) and storm events (light-colored). (Photo: Schmitt)
Further information: Professor Eberhard Gischler, Department of Geosciences, Riedberg Campus, Tel.: +49(0)69-798 40183, email: gischler@em.uni-frankfurt.de
Jul
20
2020
12:24
Faster and simpler production of high-resolution, three-dimensional electron microscopy images of biomolecules聽
How smart, ultrathin nanosheets go fishing for proteins
FRANKFURT/JENA. An interdisciplinary team from Frankfurt and Jena has developed a kind of bait with which to fish protein complexes out of mixtures. Thanks to this 鈥渂ait", the desired protein is available much faster for further examination in the electron microscope. The research team has christened this innovative layer of ultrathin molecular carbon the 鈥渟mart nanosheet". With the help of this new development, diseases and their treatment with drugs can be better understood, for example.
鈥淲ith our process, new types of proteins
can be isolated from mixtures and characterized within a week," explains Daniel
Rhinow from the Max Planck Institute of Biophysics in Frankfurt. 鈥淭o date, just
the isolation of the proteins was often part of a doctorate lasting several
years." Together with Andreas Terfort (51猎奇) and Andrey Turchanin
(Friedrich Schiller University Jena), the idea evolved a few years ago of
fishing the desired proteins directly out of mixtures by equipping a nanosheet
with recognition sites onto which the target protein bonds. The researchers
have now succeeded in making proteins directly available for examination using
electron cryo-microscopy through a 鈥渟mart nanosheet".
Electron cryo-microscopy is based on the
shock-freezing of a sample at temperatures under -150 掳C. In this process, the
protein maintains its structure, no interfering fixing and coloring agents are needed,
and the electrons can easily irradiate the frozen object. The result is high-resolution,
three-dimensional images of the tiniest structures 鈥� for example of viruses and
DNA, almost down to the scale of a hydrogen atom.
In preparation, the proteins are
shock-frozen in an extremely thin layer of water on a minute metal grid. Previously,
samples had to be cleaned in a complex procedure 鈥� often involving an extensive
loss of material 鈥� prior to their examination in an electron microscope. The electron microscopy procedure is only successful
if just one type of protein is bound in the water layer.
The research group led by Turchanin is now
using nanosheets that are merely one nanometer thick and composed of a cross-linked
molecular self-assembled monolayer. Terfort's group coats this nanosheet with a
gelling agent as the basis for the thin film of water needed for freezing. The
researchers then attach recognition sites (a special nitrilotriacetic acid group
with nickel ions) to it. The team led by Rhinow uses the 鈥渟mart nanosheets" treated
in this way to fish proteins out of a mixture. These were marked beforehand
with a histidine chain with which they bond to the recognition sites; all other
interfering particles can be rinsed off. The nanosheet with the bound protein
can then be examined directly with the electron microscope.
鈥淥ur smart nanosheets are particularly
efficient because the hydrogel layer stabilizes the thin film of water required
and at the same time suppresses the non-specific binding of interfering
particles," explains Julian Scherr of 51猎奇. 鈥淚n this way,
molecular structural biology can now examine protein structures and functions
much faster." The knowledge gained from this can be used, for example, to
better understand diseases and their treatment with drugs.
The team has patented the new nanosheets
and additionally already found a manufacturer who will bring this useful tool
onto the market.
Publication: Smart Molecular Nanosheets for Advanced Preparation of Biological
Samples in Electron Cryo-Microscopy, ACS Nano 2020, https://doi.org/10.1021/acsnano.0c03052
Julian Scherr, Zian Tang, Maria K眉llmer,
Sebastian Balser, Alexander Stefan Scholz, Andreas Winter, Kristian Parey,
Alexander Rittner, Martin Grininger, Volker Zickermann, Daniel Rhinow, Andreas Terfort
und Andrey Turchanin; Department of Structural Biology, Max Planck Institute of
Biophysics, Max-von-Laue-Str. 3, 60438 Frankfurt am Main; Faculty of
Biochemistry, Chemistry and Pharmacy, 51猎奇, Max-von-Laue-Str. 7,
60438 Frankfurt am Main; Institute of Physical Chemistry, Friedrich Schiller University
Jena, Lessingstr. 10, 07743 Jena
A picture can be downloaded under:
Caption: The new nanosheet process: The
protein complex to be examined (yellow) is attached to the smart nanosheet via
a nickel complex with the aid of a marker (red chain with pentagons). Unwanted
proteins (gray) are repelled by the hydrogel (black grid). After freezing the
entire structure, including a thin film of water, this can be irradiated with
electrons to obtain images of the bound proteins, from which a computer can then
calculate the 3D structure of the protein.
Further
information:
Professor
Andreas Terfort, Institute of Inorganic and Analytical Chemistry, 51猎奇,
Max-von-Laue-Str. 7, 60438 Frankfurt am Main, aterfort@chemie.uni-frankfurt.de,
+49-69-798-29181,
Professor Andrey Turchanin, Friedrich
Schiller University Jena, Lessingstr. 10, 07743 Jena, andrey.turchanin@uni-jena.de,
+49-3641-48370,
Jul
6
2020
18:45
X-ray structure analysis gives detailed insights into molecular factory
How do bacteria build up natural products?
FRANKFURT. The active agents of many drugs are natural products, so called because often only microorganisms are able to produce the complex structures. Similar to the production line in a factory, large enzyme complexes put these active agent molecules together. A team of Technical University of Munich (TUM) and 51猎奇 Frankfurt has now succeeded in investigating the basic mechanisms of one of these molecular factories. (Nature Chemistry, DOI: 10.1038/s41557-020-0491-7)
Many important drugs such as antibiotics or active agents against cancer are natural products which are built up by microorganisms for example bacteria or fungi. In the laboratory, these natural products can often be not produced at all or only with great effort. The starting point of a large number of such compounds are polyketides, which are carbon chains where every second atom has a double bound to an oxygen atom.
In the cell of a microorganism microbial cell such as the in the Photorhabdus luminescens bacterium, they are produced with the help of polyketide synthases (PKS). In order to build up the desired molecules step by step, in the first stage of PKS type II systems, four proteins work together in changing 鈥渢eams".
In a second stage, they are then modified to the desired natural product by further enzymes. Examples of bacterial natural products which are produced that way are, inter alia, the clinically used Tetracyclin antibiotics or Doxorubicin, an anti-cancer drug.
Interdisciplinary cooperation
While the modified steps of the second stage are well researched studied for many active agents, there have up to now hardly been any insights into the general functioning of the first stage of these molecular factories where the highly reactive polyketide intermediate product is bound to the enzyme complex and protected so that it cannot react spontaneously.
This gap is now closed by the results of the cooperation between the working groups of Michael Groll, professor of biochemistry at the Technical University of Munich, and Helge Bode, professor of molecular biotechnology at 51猎奇 Frankfurt, which are published in the renowned scientific journal Nature Chemistry.
Findings inspire to new syntheses of active agents
鈥淚n the context of this work, we were for the first time able to analyze complexes of the different partner proteins of type II polyketide synthase type II with the help of X-ray structure analysis and now understand the complete catalytic cycle in detail," Michael Groll explains.
鈥淏ased on these findings, it will be possible in the future to intervene manipulatein the central biochemical processes in a targeted manner and thus change the basic structures instead of being restricted to the decorating enzymes," Helge Bode adds.
Although it is a long way to develop improved antibiotics and other drugs, both groups are optimistic that now also the structure and the mechanism of the missing parts of the molecular fabric factory can be explained. 鈥淲e already have promising data of the further protein complexes," says Maximilian Schmalhofer, who was involved in the study as a doctoral candidate in Munich.
The work was supported with funds of the Deutsche Forschungsgemeinschaft (DFG) in the context of SPP 1617, SFB 1035 and the Center for Integrated Protein Science Munich (CIPSM) cluster of excellence and the LOEWE focus MegaSyn of the State of Hesse. X-ray structure data were measured at the Paul Scherrer Institute in Villigen (Switzerland). The Swedish National Infrastructure for Computing provided computing time for the theoretical modeling.
Publication: Alois Br盲uer, Qiuqin Zhou, Gina L.C. Grammbitter, Maximilian Schmalhofer, Michael R眉hl, Ville R.I. Kaila, Helge B. Bode und Michael Groll: Structural snapshots of the minimal PKS system responsible for octaketide biosynthesis, Nature Chemistry, DOI: 10.1038/s41557-020-0491-7, Link:
More information:
51猎奇 Frankfurt
Prof. Dr. Helge B. Bode
Molecular Biotechnology
Faculty of Biological Sciences and
Buchmann Institute for Molecular Life Sciences (BMLS)
Phone +49 (0)69 798 29557
h.bode@bio.uni-frankfurt.de
/45924717/Institute_for_Molecular_Bio_Science?locale=en
Technical University of Munich
Prof. Dr. Michael Groll
Professorship of Biochemistry
Lichtenbergstr. 4, 85748 Garching, Germany
Phone: +49 89 289 13360
michael.groll@tum.de
Jun
24
2020
11:37
Mystery about the cancer drug nelarabine solved after decades
Treating leukaemia more effectively聽
FRANKFURT. Acute
lymphoblastic leukaemia (ALL) is the most common kind of cancer in children.
T-ALL, a subtype that resembles T-lymphocytes, can be treated successfully with
the drug nelarabine. The drug has not been successful, however, with B-ALL, a
subtype resembling B-lymphocytes. Since the 1980s, oncologists have been puzzled
as to the cause of this difference. Now, an international research team headed
by 51猎奇 and the University of Kent has discovered the reason:
B-ALL cells contain the enzyme SAMHD1, which deactivates the drug.
In the current issue of 鈥淐ommunications
Biology", Professor Jindrich Cinatl from the Institute for Medical Virology at
51猎奇 and Professor Martin Michaelis from the School of Biosciences
at the University of Kent report on their investigations with nelarabine on
different cell lines. 鈥淣elarabine is the precursor of the drug, a prodrug, that
does not become effective until it is combined with three phosphate groups in
the leukaemia cell," explains Professor Cinatl. 鈥淚n studies of various ALL cell
lines and leukaemia cells from ALL patients, we have been able to demonstrate
that the enzyme SAMHD1 splits the phosphate groups off so that the medicine loses
its effect." Because B-ALL cells contain more SAMHD1 than T-ALL cells,
nelarabine is less effective with B-ALL.
These results could improve the treatment
of ALL in the future. In rare cases, B-ALL cells contain very little SAMHD1 so
that treatment with nelarabine would be possible. On the contrary, there are
also rare cases of T-ALL exhibiting a lot of SAMHD1. In such cases, the
otherwise effective nelarabine would not be the right medication. Professor
Michaelis observes: 鈥淪AMHD1 is thus a biomarker that allows us to better adapt
treatment with nelarabine to the individual situation of ALL patients."
Tamara Rothenburger, whose doctoral
dissertation was funded by the association 鈥淗ilfe f眉r krebskranke Kinder
Frankfurt e.V鈥�, is satisfied when she looks back at her research. 鈥淚 hope that
many children with leukaemia will benefit from the results." The research was
also supported by the Frankfurt Stiftung f眉r krebskranke Kinder. Additional
members of the research group are Ludwig-Maximilians-Universit盲t Munich, and
University College London.
Publication:
Tamara Rothenburger, Katie-May McLaughlin,
Tobias Herold, Constanze Schneider, Thomas Oellerich, Florian Rothweiler,
Andrew Feber, Tim R. Fenton, Mark N. Wass, Oliver T. Keppler, Martin Michaelis,
Jindrich Cinatl. SAMHD1 is a key
regulator of the lineage-specific response of acute lymphoblastic leukaemias to
nelarabine, in: Communications Biology, DOI
10.1038/s42003-020-1052-8,
Further
information:
Prof. Dr. rer. nat. Jindrich Cinatl
Institute for Medical Virology
University Hospital Frankfurt
Tel.: +49 69 6301-6409
E-mail: cinatl@em.uni-frankfurt.de