A target for a panacea
Scientists have identified a key protein that can be used to treat depression, obesity and chronic pain
Dmitry Mazalev, Naked Science
Depression, obesity and chronic pain are closely related to exposure to a single protein – FKBP51. Until now, it has been quite problematic to suppress its work without affecting other proteins, but now German researchers have developed a highly selective compound that can effectively block FKBP51 in mice, relieving chronic pain and having a positive effect on diet-induced obesity and mood. The new compound may also find use in alcoholism and brain cancer. The results were presented at the National Meeting and Exhibition of the American Chemical Society (ACS).
"The FKBP51 protein plays an important role in cases of depression, obesity, diabetes and chronic pain conditions. We have developed the first highly effective, highly selective inhibitor of FKBP51, called SAFit2, which is now being tested in mice. Thus, inhibition of FKBP51 may become a new therapeutic option for the treatment of all these conditions," says Felix Hausch, the lead author of the study, an employee of the Technical University of Darmstadt (Germany).
According to Haush, he was intrigued by the specific regulatory role that protein played in cells. FKBP51 is expressed in several places throughout the body: in the brain, skeletal muscle tissue and fat. It also has several effects: for example, protein can limit glucose uptake, leading to the body accumulating fat rather than burning it. It also affects stress responses. So, Haush and his colleagues decided that blocking this protein could be the key to the development of drugs for the treatment of various diseases.
However, FKBP51 is very similar to its closest "relative" – FKBP52. These two proteins are similar in structure, but perform opposite functions in cells: Haush calls this a "yin-yang" situation. Selectivity between the two proteins is considered critical, but this is difficult to achieve since they are very similar. In the course of the work, the experts found that FKBP51 can change its shape in a way that FKBP52 cannot, and this allowed the development of highly selective inhibitors.
The researchers used nuclear magnetic resonance techniques to detect a previously hidden binding site in FKBP51.
A new inhibitor (highlighted in orange) associated with the protein molecule FKBP51. Figure from the press release ACS Depression, obesity, chronic pain could be treated by targeting the same key protein – VM.
Now scientists are testing SAFit2, a leading inhibitor of FKBP51, which they developed during animal experiments. According to Haush, the resulting drug really helps mice cope better with stress. In mice, SAFit2 reduced stress hormone levels, promoted more active stress management, responded normally to antidepressants, protected against weight gain, helped normalize glucose levels and reduced pain in three animal models.
Scientists have a lot of work to do before it becomes possible to use FKBP51 inhibitors as a drug molecule in human testing. In the meantime, the team is also investigating FKBP51 inhibitors in other applications. The group has already conducted a number of studies in mice on the use of FKBP51 in the treatment of alcoholism, but the results are still preliminary. In addition, Haush points out that certain types of glioblastoma tumors overexpress FKBP51. He hopes that the result indicates that FKBP51 inhibitors can be used in the treatment of cancer when patients' tumors change and existing drugs for their treatment become powerless.
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