SAFit-ligands provide the foundation for a mechanistically novel treatment of stress-related psychiatric disorders
The FK506-binding protein 51 (FKBP51) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the very similar functional counterplayer FKBP52.
The SAFit-ligand (blue/green) is a highly selective inhibitor of FKBP51 (grey), a risk factor for stress-related psychiatric disorders. The binding of SAFit induces a conformational change (red protein side chain) in FKBP51, but not in its very similar functional counterplayer FKBP52.
© MPI of Psychiatry / Felix Hausch
Scientists at the Max Planck Institute of Psychiatry in Munich have now developed the first potent and highly selective inhibitor of FKBP51. The so-called SAFit-ligand inhibits FKBP51 enhancing growth of neuronal cell cultures and improving stress-coping behavior in mice. These findings provide the structural and functional basis for the development of mechanistically novel antidepressants.
FKBP51 and FKBP52 are proteins which regulate multiple cellular activities. Most importantly in the context of psychiatric diseases, they interact in an antagonistic manner with receptors for stress hormones in the brain. FKBP51 inhibits while FKBP52 enhances the activity of the glucocorticoid receptor, thus playing a major role in the regulation of stress responses.
For the first time, scientists around Felix Hausch, Project Group Leader at the Max Planck Institute of Psychiatry and lecturer at the Ludwig-Maximilians-University in Munich, developed highly selective inhibitors of FKBP51 by an induced-fit mechanism. “We initially used a chemical genetics approach and then, step by step, improved the fitting of our inhibitors,” describes Steffen Gaali, post-doctoral student in the project group of Felix Hausch and first author of the current study.
“Finally the most potent ligand SAFit, a selective Antagonist of FKBP51 by induced fit, had a more than 10,000-fold selectivity for FKBP51 over FKBP52.” SAFit exactly fits into a pocket of FKBP51 by pushing out one of the protein’s amino acid side chains. This conformational change cannot occur in the FKBP52 protein.
In further experiments, the researchers investigated the characteristics and effects of the SAFit-ligand. In cell culture, SAFit potently stimulated the differentiation of neuronal cell lines. Unlike former inhibitors of FKBP51, the new pharmacological agent did not show any immunosuppressive side-effects. Further, SAFit displayed antidepressant-like activity in mice. By inhibiting FKBP51, the protein’s inhibitory effect on the glucocorticoid receptor is reduced in the brain. Thus, SAFit enhances the regulation of one of the key stress-coping mechanisms, the HPA axis.
“Depression is likely a biologically heterogeneous disease and a major shortcoming is the inability to match antidepressant agents to the specific underlying biological alterations,” explains Felix Hausch. “Patients with FKBP51-hyperinducing gene variants or with a hyperactive HPA axis can be clinically identified by genotyping for FKBP51 and/or the Dex-CRF test.” Taken together, by generating the SAFit-inhibitor, the Max Planck scientists provide the proof-of-principle for selective FKBP51 inhibitors as a mechanistically novel treatment for stress-related psychiatric disorders.
The hypothalamic–pituitary–adrenal axis (HPA axis) is a complex set of interactions among the hypothalamus, the pituitary gland and the adrenal glands. The interactions among these organs play a major role in the control of reactions to stress and regulate many processes, including digestion, the immune system, mood or emotions. The stress-induced release of corticotropin-releasing factor (CRF) by the hypothalamus leads to increased cortisol production in the adrenal glands. Cortisol itself facilitates an adaptive phase in which alarm reactions including the immune response are suppressed, allowing the body to attempt countermeasures against the stress.
The activity of the HPA axis can be measured with the Dex-CRF test. The release of cortisol is significantly higher in some groups of depressed patients than in non-depressed controls, indicating hyperactivity of the HPA axis.
Max Planck Institute of Psychiatry, München
Dr. Anna Niedl
Press and Public Relations
Max Planck Institute of Psychiatry, München
Phone: +49 89 30622-263
Fax: +49 89 30622-370
S. Gaali, A. Kirschner, S. Cuboni, J. Hartmann, C. Kozany, G. Balsevich, C. Namendorf, P. Fernandez-Vizarra, C. Sippel, A.S. Zannas, R. Draenert, E.B. Binder, O.F.X. Almeida, G. Rühter, M. Uhr, M.V. Schmidt, C. Touma, A. Bracher, F. Hausch.
Selective inhibitors for the psychiatric risk factor FKBP51 enabled by an induced-fit mechanism
Nature Chemical Biology, 1. December 2014
Felix Hausch | Max-Planck-Institute
Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University
The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy