Depression, obesity and chronic pain are closely related to exposure to the same 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 nutritional obesity and mood. The new compound can also be used in alcoholism and brain cancer. The results were presented at the National Assembly and at the exhibition of the American Chemical Society (American Society of ChemistryACS).
"Protein FKBP51 plays an important role in cases of depression, obesity, diabetes and chronic pain conditions. We developed the first highly effective and highly selective inhibitor FKBP51named SAFit2which is now being tested in rats. Thus, inhibition FKBP51 may become a new therapeutic option to treat all these conditions, "says Felix Hausch, lead author of the study, an official at the Technical University of Darmstadt, Germany.
According to Hausch, he was intrigued by the specific regulatory role that the protein played in cells. FKBP51 expressed in various places in the body: in the brain, skeletal muscle tissue and fat. It also has several effects: for example, the protein can limit the absorption of glucose, causing the body to accumulate fat, instead of burning it. It also affects stress reactions. Therefore, Hausch and his colleagues decided that the blockade of this protein could be the key to the development of drugs for the treatment of various diseases.
A new inhibitor (highlighted in orange) is considered selective for FKBP51, which is associated with depression, chronic pain and obesity / © Felix Hausch
However FKBP51 very similar to your nearest "relative" FKBP52. These two proteins are similar in structure but play opposite roles in cells: Hausch calls this the Yin-Yang situation. The selectivity between two proteins is considered critical, but this is difficult to achieve because they are very similar. In the course of the work, experts FKBP51 can change its shape as FKBP52 can not, allowed the development of highly selective inhibitors.
The researchers used nuclear magnetic resonance techniques to detect a previously hidden binding site in FKBP51. Scientists are now testing SAFit2main inhibitor FKBP51that they developed during animal experiments. According to Hausch, the resulting drug really helps the mice cope better with stress. In mice SAFit2 reduced stress hormone levels, contributed to more active coping with stress, responded normally to antidepressants, protected against weight gain, helped normalize blood glucose levels and reduced pain in three animal models.
Scientists have a lot of work to do before it is possible to use inhibitors FKBP51 as a drug molecule when tested on humans. Meanwhile, the team is also investigating inhibitors FKBP51 in other applications. The group has already conducted several studies with mice on the use of FKBP51 in the treatment of alcoholism, but the results are preliminary. In addition, Hausch indicates that certain types of glioblastoma tumors overexpress FKBP51. He expects the result to indicate that inhibitors FKBP51 can be used in the treatment of cancer when patients' tumors are modified and existing drugs for treatment become impotent.