Same Key Protein Responsible For Depression, Obesity, Chronic Pain

Researchers have found a way to target the key protein in mice without affecting similar proteins.

It has been long known that one key protein, called "FK506-binding protein 51" or FKBP51, was responsible for major depression, obesity, and chronic pain. What was not know however was how to target the protein without affecting similar proteins. 

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Blocking FKBP51

Now, researchers have developed a highly selective compound that can effectively block FKBP51 in mice. The result is a relief from chronic pain as well as an improvement in weight gain and mood.

"The FKBP51 protein plays an important role in depression, obesity, diabetes, and chronic pain states," said Felix Hausch, Ph.D., the project's principal investigator.

"We developed the first highly potent, highly selective FKBP51 inhibitor, called SAFit2, which is now being tested in mice. Inhibition of FKBP51 could thus be a new therapeutic option to treat all of these conditions."

FKBP51 has multiple effects such as restricting the uptake of glucose leading the body to store fat instead of burning it. It also influences stress responses.

So, Hausch and his team stipulated that blocking this protein could be the key to developing drugs to treat several conditions. But there was the danger of also affecting FKBP51's closest protein cousin, FKBP52.

"These two proteins are very similar in structure, but they are doing opposing things in cells," Hausch said. 

"We have this yin-yang situation. Selectivity between these two proteins is thought to be crucial, but this is hard to achieve since the two proteins are so similar. We discovered that FKBP51 can change its shape in a way that FKBP52 can't, and this allowed the development of highly selective inhibitors."

A lead FKBP51 inhibitor

From there they developed a lead FKBP51 inhibitor called SAFit2. Now, they are in the process of testing it on animals. "It indeed helps mice cope better in stressful situations," Hausch said.

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In mice, SAFit2 has some truly impressive results. It reduces stress hormone levels, stops weight gain, helps normalize glucose levels and reduces pain.

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Hausch and his team are also looking at FKBP51 inhibitors in other applications. So far, the group has undertaken a number of mouse studies on the involvement of FKBP51 in alcoholism and Hausch also revealed that FKBP51 inhibitors could be used in cancer treatment.

He hopes that these inhibitors could help when patients' tumors mutate beyond current drugs' capacity to treat them. "We may be able to resensitize them to different types of chemotherapy using these specific inhibitors," he said.

Unfortunately, a lot more work needs to be done before these inhibitors could be ready for human testing, said Hausch.

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