Most drugs operate by binding to one or more proteins and affecting their function, which creates two common bottlenecks in the development of drugs; identifying the right target proteins and designing drug molecules able to efficiently seek out and bind to them.
This illustration shows the path of a drug from a pill to a drug target.
Credit: Daniel Martinez Molina
No method has been available for directly measuring the efficiency of the drug molecules to locate and bind to its target protein. Now researchers from Karolinska Institutet have developed a new tool called CETSA (Cellular Thermal Shift Assay), which utilise the concept that target proteins usually get stabilised when drug molecules bind.
"We have shown that the method works on a wide variety of target proteins and allows us to directly measure whether the drug molecules reach their targets in cells and animal models," says lead investigator Professor Pär Nordlund of the Department of Medical Biochemistry and Biophysics. "We believe that CETSA will eventually help to improve the efficiency of many drugs and contribute to better drug molecules and more successful treatments."
The lack of methods to directly measure the binding of a drug to its target protein has caused a degree of uncertainty in many phases of drug development. In some cases, where drug candidates have not lived up to expectations in clinical trials on humans, it has transpired that the drug molecules have failed to bind to the right protein. The group behind the study believes that CETSA will be an important control stage and a complement to other methods.
In the present study, the researchers also examined processes that can lead to drug resistance in cells. The team believes that by virtue of its ability to determine whether existing drugs are suitable for individual patients, the method is of potential value to the practice of individualised treatment.
"We believe that the method can provide an important diagnostic tool in the treatment of cancer, for example, as CETSA can, in principle, enable us to determine which drug is most effective at targeting the proteins in the tumour," says Daniel Martinez Molina at the Department of Medical Biochemistry and Biophysics, who leads a team in the project aiming at establishing CETSA for patient studies. "This also makes it possible for clinicians to ascertain at an early stage of treatment whether the tumour has developed a certain kind of resistance and which type of therapy could then be more suitable for the patient."
The evaluation of CETSA has been conducted in collaboration with Yihai Cao's research group at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet, Pelago Bioscience AB and Nanyang Technological University in Singapore. Professor Pär Nordlund and Dr Daniel Martinez Molina are two of the founders of the company, which was also involved in the study. The project was financed by external grants from the Swedish Research Council, the Swedish Cancer Society and the European Research Council.
Publication: 'Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay', Daniel Martinez Molina, Rozbeh Jafari, Marina Ignatushchenko, Takahiro Seki, E. Andreas Larsson, Chen Dan, Lekshmy Sreekumar, Yihai Cao, Pär Nordlund, Science 5 July 2013.
Contact the Press Office and download images: ki.se/pressroom
Karolinska Institutet – a medical university: ki.se/english
Press Office | EurekAlert!
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences