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Mechanism of new small molecule inhibitors for the treatment of depression, pain and obesity decoded


Researchers at TUM and the Helmholtz Zentrum München have moved a step closer towards developing innovative drug molecules for the treatment of psychiatric diseases. They discovered how inhibitors inactivate a special protein that plays a key role in various diseases. Their approach can be applied to other medically relevant proteins where the development of specific inhibitors has proved difficult up to now. The research effort was led by Michael Sattler, Director of the Institute of Structural Biology at the Helmholtz Zentrum München and Professor of Biomolecular NMR-Spectroscopy at TUM as well as Principal Investigator at the MSB.

At first sight, depression, chronic pain and obesity appear to be separate diseases. However, various studies have shown that a protein named FKBP51 plays a key role in all three disorders. Consequently, the FKBP51 protein was already recognized as a target structure for pharmaceutical therapy.

There is only one catch: FKBP51 cannot simply be inhibited by a small molecule because its receptor antagonist, protein FKBP52, is too similar in structure. Whereas FKBP52 increases the activity of glucocorticoid receptors (glucocorticoid receptors are binding sites for steroid hormones), FKBP51 has an inhibiting effect on them. Glucocorticoid receptors are the stress hormone receptors in the brain. Prolonged activation of these receptors can lead to psychiatric diseases. Development of a selective inhibitor that can differentiate between both proteins and selectively inhibit only one of them is therefore crucial for developing drug molecules without unwanted side effects. Or to use another analogy, it is rather like having to develop a specific key that only fits into the FKBP51 keyhole, but not into the FKBP52 one.

Back in 2014, Felix Hausch from the Max Planck Institute of Psychiatry developed the highly specific inhibitor SAFit in order to switch off the FKBP51 protein but not FKBP52. "The underlying mechanism for the selectivity was, however, unknown," says Michael Sattler.


What effect do inhibitors have on FKBP51? 

In order to clarify this question, Prof. Sattler and his colleagues combined different methods. With the aid of nuclear magnetic resonance (NMR) spectroscopy, the internal mobility of the FKBP51 protein was determined in order to examine what role this plays for the SAFit inhibitor. In addition, they carried out biophysical measurements to determine the affinity and kinetic binding rates that lead to binding, and also performed mutation analyses. If individual letters (nucleotides) in the corresponding gene are replaced, proteins with specific amino acid changes and thus different properties are produced. It can thus be seen which of the protein’s amino acids are required in order to promote the binding of an inhibitor to the target protein. 

“We discovered that SAFit molecules bind to a transient pocket in FKBP51 that is normally hidden and not accessible,” Sattler reports. “The binding site is blocked by an amino acid and is only accessible in fewer than 1% of all molecules. However, NMR experiments demonstrated that the blocking amino acid is dynamic and sometimes allows access to the binding cavity. SAFit molecules can now exploit this for binding to the pocket. Once bound, the inhibitor then inactivates the FKBP51 protein. As no such dynamic pocket exists in FKBP52, the SAFit inhibitors cannot bind to this protein.

Sattler speaks of a “crucial step” in the development of new drugs. “The concept that has been discovered here and our methodology can now be applied to other proteins where it is difficult to develop selective inhibitors,” he notes. “This will open up new possibilities for many diseases with unmet medical needs.”

The research teams led by Felix Hausch, now at TU Darmstadt, and Michael Sattler will now continue with their approach and develop the concept as part of a LOEWE research proposal, which has just been approved by the federal state of Hesse.


This article is based on a release published by the Helmholtz Zentrum München.


Jagtap PKA et al, Selective inhibitors of FKBP51 employ conformational selection of dynamic invisible, Angewandte Chemie International Edition, Doi: 10.1002/anie.201902994




Scientific Contact:

Prof. Michael Sattler
Technical University of Munich
Chair of Biomolecular NMR-Spectroscopy
Phone: +49 89 289 52600
Email: michael.sattler@tum.de 

Media Relations MSB: 

Dr. Paul Piwnicki 
Phone: +49 89 289 10808
Email: paul.piwnicki@tum.de