Depression, obesity, chronic pain could be treated by targeting the same key protein

Major depression, obesity, and chronic pain are all related to the effects of a protein, called "FK506 binding protein 51," or FKBP51. Until now, the difficulty of finding something specific enough to do the job and not affecting similar proteins was hindering efforts to inhibit this target. At present, a research group has developed a highly selective compound capable of effectively blocking FKBP51 in mice, thus relieving chronic pain and having positive effects on obesity and mood induced by # 39; s feed. The new compound could also have applications in alcoholism and brain cancer.

The researchers will present their findings today at the 2019 Spring National Meeting and Exposition of the American Chemical Society (ACS).

"FKBP51 protein plays an important role in depression, obesity, diabetes and chronic pain," says Felix Hausch, Ph.D., the project's lead researcher. "We have developed the first highly potent and highly selective FKBP51 inhibitor, called SAFit2, which is currently being tested in mice, so the inhibition of FKBP51 could be a new therapeutic option to treat all these problems."

Hausch, who is at the Technical University of Darmstadt, started the project when studies were published linking the protein to depression. "The particular regulator role that he seemed to play in the cells intrigued me," he said. "And there was a known natural product that could serve as a starting point, and together it looked like an interesting protein to work on."

FKBP51 is expressed in multiple places in the body, such as the brain, skeletal muscle tissue and fat. It also has multiple effects. For example, proteins can limit the absorption of glucose and browning fats, so that the body stores fat instead of burning it. It also affects stress responses. Thus, Hausch and his colleagues understood that blocking this protein could be the key to developing drugs to treat various conditions.

But FKBP51 looks a lot like its closest protein cousin, FKBP52. "These two proteins have a very similar structure, but they act in opposite ways in cells," says Hausch. "We have this yin-yang situation, the selectivity between these two proteins is considered crucial, but this is difficult to obtain because the two proteins are so similar." We discovered that FKBP51 could change shape in the same way and that has allowed the development of highly selective inhibitors. "

Researchers have now used nuclear magnetic resonance techniques to detect a previously hidden binding site in FKBP51. The approach could help other researchers identify similar "cryptic" binding sites in difficult drug targets in the future, Hausch said.

His team is currently testing SAFit2, the main inhibitor of FKBP51 developed from these studies, in the animal. "It helps mice cope better with stressful situations," says Hausch. In mice, SAFit2 reduced stress hormone levels, promoted a more active adaptation to stress, was synergistic with antidepressants, protected against weight gain, helped normalize glucose levels and reduced pain in three animal models.

According to Hausch, much remains to be done to bring FKBP1 inhibitors to the point where they could be used as a drug molecule for human testing. Meanwhile, the team is also exploring inhibitors of FKBP51 in other applications. Until now, the group has conducted a number of studies in mice on the involvement of FKBP51 in alcoholism, but the results are still preliminary. In addition, Hausch points out that some types of glioblastoma tumors overexpress FKBP51. He hopes this result indicates that FKBP51 inhibitors could be used in the treatment of cancer, when patients' tumors mutate beyond the ability of current drugs to treat them. "We may be able to sensitize them to different types of chemotherapy using these specific inhibitors," he said.

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More information:
FKBP51 Selective FKBP51 Inhibitors Activated by Transient Pocket Link, National Chemical Spring (2019) Spring Meeting and Meeting of the American Chemical Society (ACS).