Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Tailor-made pharmaceuticals as basis for novel antidepressants

02.12.2014

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.


Contact

Felix Hausch
Max Planck Institute of Psychiatry, München
Email: hausch@psych.mpg.de


Dr. Anna Niedl
Press and Public Relations

Max Planck Institute of Psychiatry, München
Phone: +49 89 30622-263

Fax: +49 89 30622-370

Email: anna_niedl@psych.mpg.de


Original publication
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

Source

Felix Hausch | Max-Planck-Institute

More articles from Health and Medicine:

nachricht Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

From rocks in Colorado, evidence of a 'chaotic solar system'

23.02.2017 | Physics and Astronomy

'Quartz' crystals at the Earth's core power its magnetic field

23.02.2017 | Earth Sciences

Antimicrobial substances identified in Komodo dragon blood

23.02.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>