Press releases 鈥� 2021
Jan
28
2021
14:02
International research team investigates the binding kinetics of kinase inhibitors
Pharmaceutical research: when active substance and target protein 鈥渆mbrace鈥� each other
Scientists at 51猎奇 Frankfurt, together
with colleagues from Darmstadt, Heidelberg, Oxford and Dundee (UK), have
investigated how the fit of potent inhibitors to their binding sites can be
optimised so that they engage longer with their target proteins. Long target
residency has been associated with more efficient pharmacological responses for
instance in cancer therapy. The result: High resolution structures revealed that
when the interaction between the inhibitors and the target proteins lasts
particularly long, the target proteins "nestle" against the inhibitors.
In future, the researchers want to use computer simulations to predict the residence
time of inhibitors during drug development.
FRANKFURT. Many
anti-cancer drugs block signals in cancer cells that help degenerated cells to
multiply uncontrollably and detach from tissue. For example, blocking the
signalling protein FAK, a so-called kinase, causes breast cancer cells to
become less mobile and thus less likely to metastasise. The problem is that
when FAK is blocked by an inhibitor, the closely related signalling protein
PYK2 becomes much more active and thus takes over some of FAK's tasks. The
ideal would therefore be an inhibitor that inhibits both FAK and PYK2 in the
same way for as long as possible.
An international team led by the pharmaceutical
chemist Prof. Stefan Knapp from 51猎奇 has investigated a series of
specially synthesised FAK inhibitors. All inhibitors bound to the FAK protein
at about the same rate. However, they differed in the duration of binding: The
most effective inhibitor remained bound to the FAK signalling protein the
longest.
Using structural and molecular biological
analyses as well as computer simulations, the research team discovered that binding
of inhibitors that remain in the FAK binding pocket for a long time induce a
structural change. Thus, through binding of these inhibitors, FAK changes its
shape and forms a specific, water-repellent structure at contact sites with the
inhibitor, comparable to an intimate embrace.
The closely related protein PYK2, on the
other hand, remained comparatively rigid, and although the most effective FAK
inhibitor also blocked PYK2, its effect was significantly weaker due to quickly
dissociating inhibitors from the binding site. Interestingly, computer
simulations were able to predict the kinetics of binding very well, providing a
method for accurate simulation of drug dissociation rates for future optimisation
of drug candidates.
Prof. Stefan Knapp explains: "Because
we now have a better understanding of the molecular mechanisms of the
interaction of potent inhibitors of these two kinases, we hope to be able to
use computer simulations to better predict drug residence times of inhibitors
and drugs candidates in the future. So far, little attention has been paid to
the kinetic properties of drug binding. However, this property has now emerged
as an important parameter for the development of more effective drugs that are
designed to inhibit their target proteins - as in the case of FAK and PYK2 -
not only potently but also for a long time."
Publication:
Benedict-Tilman Berger, Marta Amaral,
Daria B. Kokh, Ariane Nunes-Alves, Djordje Musil, Timo Heinrich, Martin
Schr枚der, Rebecca Neil, Jing Wang, Iva Navratilova, Joerg Bomke, Jonathan M.
Elkins, Susanne M眉ller, Matthias Frech, Rebecca C. Wade, Stefan Knapp: Structure-kinetic relationship reveals the
mechanism of selectivity of FAK inhibitors over PYK2. Cell Chemical Biology
This work was carried out within the
framework of the public-private partnership K4DD (Kinetics for Drug Discovery)
of the Innovative Medicinces Initiatives (IMI).
Images
for download:
Picture with and without text:
Caption:
Upper
part: Long residence time. An inhibitor
(left: stick model) binds to the signal molecule FAK (right: part oft the FAK
protein depicted as calotte model with spheres). The structural change of FAK
causes hydrophobic contacts (yellow, so-called DFG motif) and a long-lasting
engagement.
Lower
part: Short residence time. PYK2 signal protein
does not change its structure upon inhibitor binding, thus resulting in a fast
inhibitor dissociation. Graphics: Knapp Laboratory, 51猎奇 Frankfurt
Further
information:
Professor Stefan Knapp
Institute for Pharmaceutical Chemistry
51猎奇 Frankfurt
Germany
knapp@pharmchem.uni-frankfurt.de
Jan
28
2021
13:49
2021 Paul Ehrlich and Ludwig Darmstaedter Prize聽
Michael R. Silverman and Bonnie L. Bassler win prestigious award for their discoveries concerning the cell-to-cell communication in bacteria.
Bacteria
act in groups to accomplish feats that are impossible to achieve if a single
bacterium acts alone. For example, pathogenic bacteria act collectively to synthesize
toxins to attack the host and to encase themselves in a shield that protects
them from the host immune system and allows them to resist antibiotic treatment.
To do this, bacteria communicate with each other with chemical 鈥渨ords", count
their numbers, and act in synchrony when they have sufficient cell numbers for
success. The award winners have discovered the dictionary and syntax underlying
bacterial communication, opening up new and unprecedented opportunities to
fight bacterial infections.
FRANKFURT am MAIN. Two American scientists,
Bonnie L. Bassler and Michael R. Silverman, receive the 2021 Paul Ehrlich
and Ludwig Darmstaedter Prize, which is endowed with 120,000 鈧�. Bassler is
Professor at Princeton University and a Howard Hughes Medical Institute Investigator,
Michael R. Silverman is Emeritus Professor of the Agouron Institute in La
Jolla. The two researchers are honoured for their ground-breaking discoveries concerning
bacterial "quorum sensing", which refers to sophisticated systems of
cell-to-cell communication that bacteria use to coordinate group behaviours.
The award ceremony in St. Paul's Church, which is traditionally held on March
14, Paul Ehrlich's birthday, has been postponed due to the Coronavirus
pandemic. Instead, Bassler and Silverman will receive the award at the ceremony
in 2022.
"Silverman and Bassler have shown that, as
for multicellular organisms, collective behaviour is the rule among bacteria, rather
than the exception," wrote the Scientific Council in substantiating its
decision. "Bacteria talk to each other, they eavesdrop on other bacteria, and
they may even join forces. But: This ubiquitous chitchat, whose molecular
underpinnings were discovered by Bassler and Silverman, also represents a
previously unappreciated Achilles' heel in combating harmful microbes. Instead
of killing bacteria with antibiotics, substances may be developed that
interfere with bacterial communication effectively reducing their collective fitness.
The prize-winners' research thus has considerable relevance for medicine".
Bacteria are extremely communicative. They send
and receive chemical messages to find out whether they are alone or if additional
members of their or other species are present in the vicinal community. To take
a census of cell numbers, bacteria produce and release chemical signal
molecules that accumulate in step with increasing cell numbers. When a
threshold level of the chemical signal is achieved, the bacteria detect its
presence. In response to it, in unison, bacteria undertake behaviours that are
only productive when carried out in synchrony by the group, but not when
enacted by a single bacterium acting in isolation. This chemical
communication process is called quorum sensing and it controls hundreds of
collective activities across the bacterial kingdom.
In the 1980s, Silverman discovered the first quorum-sensing
circuit in the bioluminescent marine bacterium Vibrio fischeri. He identified
the genes and proteins enabling production and detection of the extracellular
signal molecule. He defined how the components functioned to promote collective
behaviour. In the case of Vibrio fischeri, group-wide behaviour
is the production of blue-green bioluminescence. Today, we know that quorum
sensing is the norm in the bacterial world. Indeed, there are thousands of
bacterial species that possess genes nearly identical to those discovered by
Silverman. In all of these cases, these components allow bacteria to engage in
group behaviours.
In the early 1990s, Bonnie
Bassler proved that bacteria were 鈥渕ultilingual" and that they conversed with
multiple chemical signal molecules. One communication molecule that Bassler
discovered and named autoinducer- 2 enables bacteria to communicate across species
boundaries. She went on to demonstrate that bacteria use
quorum-sensing-mediated communication to differentiate self from
other, showing that a sophisticated trait thought to be the purview of higher
organisms, in fact, evolved in bacteria billions of years ago. In recent years,
Bassler has shown that quorum sensing transcends kingdom boundaries as viruses
and host cells, including human cells, engage in this ubiquitous chit-chat. She
and other researchers also demonstrated that pathogenic bacteria rely on quorum
sensing to be virulent. Bassler developed anti-quorum-sensing strategies that,
in animal models, halt infection from bacterial pathogens of global
significance.
鈥淭he full significance of the discoveries of
the two laureates for microbiology and medicine has only recently been
recognized," says Professor Thomas Boehm, Director at the Max Planck
Institute for Immunobiology and Epigenetic and Chairman of the Scientific
Council. "Decades of meticulous and painstaking work, showed that essentially
all bacteria master the art of cell-to-cell communication," says Boehm.
"What began with work on Vibrio fischeri and Vibro harveyi led
to a fundamental change in perspective in bacteriology, and now opens up new and
unprecedented opportunities in dealing with antibiotic resistance".
Short biography Professor Dr.
Bonnie L. Bassler Ph.D. (58).
Bonnie Bassler is a microbiologist. She studied
biochemistry at the University of California at Davis and received her Ph.D.
from the Johns Hopkins University in Baltimore. She joined the laboratory of
Michael Silverman at the Agouron Institute in La Jolla as a postdoctoral fellow
in 1990. She has been at Princeton University since 1994. Bonnie Bassler is a
member of the National Academy of Sciences, the National Academy of Medicine,
and the Royal Society. She is a researcher at the Howard Hughes Medical
Institute and Squibb Professor and Chair of the Department of Molecular Biology
at Princeton University. President Obama appointed her to a six-year term on
the United States National Science Board. She has received more than twenty prestigious
national and international awards.
Short biography Professor
Michael R. Silverman, Ph.D. (77).
Michael Silverman is a microbiologist. He
studied chemistry and bacteriology at the University of Nebraska at Lincoln and
received his Ph.D. in 1972 from the University of California at San Diego.
During the period from 1972-1982, Silverman made seminal contributions to the
understanding of bacterial motility and chemotaxis. From 1982 until his
retirement, he worked at the Agouron Institute in La Jolla, of which he is a
co-founder.
The Paul Ehrlich and Ludwig
Darmstaedter Prize
The Paul Ehrlich and Ludwig Darmstaedter Prize
is traditionally awarded on Paul Ehrlich's birthday, March 14, in the
Paulskirche, Frankfurt. It honors scientists who have made significant
contributions in Paul Ehrlich's field of research, in particular immunology,
cancer research, microbiology, and chemotherapy. The Prize, which has been
awarded since 1952, is financed by the German Federal Ministry of Health, the
State of Hesse, the German association of research-based pharmaceutical company
vfa e.V. and specially earmarked donations from the following companies,
foundations and organizations: Else Kr枚ner-Fresenius-Stiftung, Sanofi-Aventis
Deutschland GmbH, C.H. Boehringer Pharma GmbH & Co. KG, Biotest AG, Hans und Wolfgang
Schleussner-Stiftung, Fresenius SE & Co. KGaA, F. Hoffmann-LaRoche Ltd.,
Gr眉nenthal GmbH, Janssen-Cilag GmbH, Merck KGaA, Bayer AG, Holtzbrinck
Publishing Group, AbbVie Deutschland GmbH & Co. KG, die
Baden-W眉rttembergische Bank, B. Metzler seel. Sohn & Co. and
Goethe-Universit盲t. The prizewinners
are selected by the Scientific Council of the Paul Ehrlich Foundation.
The
Paul Ehrlich Foundation
The
Paul Ehrlich Foundation is a legally dependent foundation which is managed in a
fiduciary capacity by the Association of Friends and Sponsors of the Goethe
University, Frankfurt. The Honorary Chairman of the Foundation, which was
established by Hedwig Ehrlich in 1929, is Professor Dr. Katja Becker, president
of the German Research Foundation, who also appoints the elected members of the
Scientific Council and the Board of Trustees. The Chairman of the Scientific
Council is Professor Thomas Boehm, Director at the Max Planck Institute of
Immunobiology and Epigenetics in Freiburg, the Chair of the Board of Trustees
is Professor Dr. Jochen Maas, Head of Research and Development and Member of
the Management Board, Sanofi-Aventis Deutschland GmbH. Professor Wilhelm
Bender, in his function as Chair of the Association of Friends and Sponsors of the
51猎奇, is Member of the Scientific Council. The President of the 51猎奇 is at the same time a member of
the Board of Trustees.
Further
information:
You can obtain selected
publications, the list of publications and a photograph of the laureate from
Dr. Hildegard Kaulen, phone: +49 (0)6122/52718, email: h.k@kaulen-wissenschaft.de and at
Background on the
award of the 2021 Paul Ehrlich and Ludwig Darmstaedter Prize to Professor
Bonnie L. Bassler, Ph.D. and Professor Michael R. Silverman, Ph.D.
Jan
28
2021
13:37
The 2021 Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers聽
Elvira Mass receives prestigious award for her research on organ development in mice聽
The course for organ health is set in the
early embryo. This year's laureate has shown that
specialized immune cells from the yolk sac accompany organ development and
contribute to maintaining their health throughout life. For Elvira Mass, impaired
function of these immune cells might cause many diseases.
Frankfurt am Main. Developmental biologist
Professor Elvira Mass, Ph.D. from the Life and Medical Sciences Institute
(LIMES) at the University of Bonn, receives the 2021 Paul Ehrlich and Ludwig
Darmstaedter Prize for Young Researchers, which is endowed with 鈧�60,000. The award ceremony in
Paulskirche, which is traditionally held on March 14th, Paul Ehrlich's
birthday, has been canceled this year due to the coronavirus pandemic. Elvira Mass will be
honored next year together with the award winners of 2022.
For organs to stay healthy and functional, they must
be constantly surveilled for abnormalities. Until a few years ago, it was believed that
this task is performed by immune cells originating from the bone marrow. In a series of elegant genetic
labelling experiments, Mass has shown that these cells are mainly yolk sac-derived
progenitor cells that migrate to the developing organs, where they immediately differentiate
and self-maintain for a lifetime. The reason for their longevity is still a mystery. These immune cells are referred to as tissue-resident
macrophages and belong to our innate immune system. Their primary job is to
scavenge anything that does not belong to a healthy organ. However, they also
produce a broad range of bioactive molecules and growth factors, ensuring that tissues
are not only 'tidy' but grow, develop, and function.
"The special achievement of Elvira Mass is to
have contributed to an important change in perspective when looking at the
function of organs," writes the Scientific Council, chaired by Professor
Thomas Boehm, Director at the Max Planck Institute for Immunobiology and
Epigenetics in Freiburg, in substantiating its decision. 鈥淚n order to understand
how organs develop and what keeps them healthy, one no longer only looks at the
bone marrow, but also at the yolk sac and thus at a completely different
population of macrophages. This observation has important implications for medicine,
because organ-specific defects might be associated with malfunctioning tissue-resident
macrophages originally derived from the yolk sac".
Mass has provided evidence for the
health-promoting function of resident macrophages in the mouse brain. Her attempt to
manipulate microglia, as the brain-specific macrophages are called, were stimulated
by the findings in patients suffering from a rare form of cancer called histiocytosis. This
cancer arises from mutated macrophages, which multiply out of control. Many patients
suffering from histiocytoses eventually develop neurodegenerative symptoms or behavioural
deficits. Mass introduced the mutation typical for histiocytosis specifically into yolk
sac-derived tissue-resident macrophages of mice and followed the development of
the animals. She found that the mutated microglia cells no longer carried out their
traditional tasks but instead attacked and eliminated neurons in their
vicinity. Eventually, this led to paralysis demonstrating that mutated microglia can cause
neurodegeneration in mice.
With funding recently awarded by the European
Research Council, Mass will investigate which environmental factors change the
epigenetic imprinting of the yolk sac-derived tissue-resident macrophages and
how these changes affect the health of organs. To this end, she will, among
other things, examine the influence of nanoplastics on macrophages. Particles that are
smaller than 500 nanometers enter the embryo's blood via the placenta and could
potentially damage the supporting function of the tissue-resident macrophages.
Short biography of Professor Dr. Elvira Mass
Elvira Mass (34) studied biology at the University
of Bonn and did her Ph.D thesis at the Life and Medical Sciences Institute
(LIMES) in Bonn. In 2014, she moved to Frederic Geissmann's laboratory at King's College in
London and followed him a few months later to the Memorial Sloan-Kettering
Cancer Center in New York. From there she returned to the LIMES Institute in
2017 as a group leader. In 2019, she became W2 Professor for
"Integrated Immunology" at the University of Erlangen-Nuernberg. In 2020, she switched
to a W2 / W3 professorship at the LIMES Institute. Mass has received
several awards, including the Heinz Maier Leibnitz Prize in 2020, which is considered
the most important award for young scientists in Germany.
Paul Ehrlich and Ludwig
Darmstaedter Prize for Young Researchers
The Paul Ehrlich and Ludwig Darmstaedter Prize
for Young Researchers, awarded for the first time in 2006, is conferred once a
year by the Paul Ehrlich Foundation on a young investigator working in Germany
for his or her outstanding achievements in the field of biomedical research.
The prize money must be used for research purposes. University faculty members
and leading scientists at German research institutions are eligible for
nomination. The selection of the prizewinner is made by the Scientific Council
on a proposal by the eight-person selection committee.
The Paul Ehrlich Foundation
The
Paul Ehrlich Foundation is a legally dependent foundation which is managed in a
fiduciary capacity by the Association of Friends and Sponsors of the Goethe
University, Frankfurt. The Honorary Chairman of the Foundation, which was
established by Hedwig Ehrlich in 1929, is Professor Dr. Katja Becker, president
of the German Research Foundation, who also appoints the elected members of the
Scientific Council and the Board of Trustees. The Chairman of the Scientific
Council is Professor Thomas Boehm, Director at the Max Planck Institute of
Immunobiology and Epigenetics in Freiburg, the Chair of the Board of Trustees
is Professor Dr. Jochen Maas, Head of Research and Development and Member of
the Management Board, Sanofi-Aventis Deutschland GmbH. Professor Wilhelm
Bender, in his function as Chair of the Association of Friends and Sponsors of
the 51猎奇, is Member of the Scientific Council. The President of
the 51猎奇 is at the same time a member of the Board of Trustees.
Further
information:
You can obtain selected
publications, the list of publications and a photograph of the prizewinner from
Dr. Hildegard Kaulen, phone: +49 (0) 6122/52718, e-mail:
h.k@kaulen-wissenschaft.de and at .
Background on the award of the 2021 Paul Ehrlich
and Ludwig Darmstaedter Prize for Young Researchers to Professor Elvira Mass,
Ph.D (PDF)