Enzyme discovery may lead to new diabetes and obesity drugs

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Discoveries about a special enzyme could pave the way for new drugs to treat diabetes and obesity, research shows. The study also finds, however, that certain existing cancer drugs meant to inhibit the enzyme don’t work as well as previously thought.

Almost all medical treatments are based on drugs that inhibit the activity of proteins in the body leaving them unable to contribute to the development of, for example, tumors, inflammatory diseases, or metabolic disorders such as diabetes and obesity.

A number of drugs that target a group of proteins—the so-called HDAC enzymes—have attracted significant attention in recent years from researchers and drug developers, because they contribute to the development of resistance towards cancer treatments.

The new research demonstrates that they also play a crucial role in a whole range of other diseases that are due to dysregulation of human genes.

The researchers have been investigating all the 11 HDAC enzymes expressed in human cells to develop specific molecules that can bind to the enzymes and block their activity in the body.

As reported in Cell Chemical Biology, researchers conducted a wide range of tests using chemically designed molecules to reveal the activities of HDAC enzymes and provide insights into their function at the molecular level. To their surprise, they made a number of new discoveries related to the HDAC11 enzyme.

“We have found a handle that will enable the identification of new inhibitors and this could potentially play a vital role in the development of drugs to treat several diseases,” says Christian Adam Olsen of the Center for Biopharmaceuticals at the University of Copenhagen.

The study shows that HDAC11 can cleave unexpected modifications on the surface of proteins. Proteins consist of long chains of 20 different amino acids in different sequences produced by the ribosome. The surfaces of proteins are also subsequently chemically modified in cells. It turns out now that HDAC11 affects specific variants of these modifications.

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By constructing chemical molecules that can bind to and regulate HDAC11, researchers can inhibit disease-causing mechanisms and the body’s production of damaged cells.

The researchers also investigated a range of existing drugs for treating hematological cancers, including leukemia and lymphoma, and other well-known HDAC inhibitors. Several of the existing inhibitors were unable to block the newly-discovered enzymatic activity of HDAC11.

“This was the second major surprise in the study and suggests that the efficacy of HDAC-targeting drugs against the HDAC11 enzyme should be reassessed. For a long time, many HDAC inhibitors were believed to affect HDAC11 but we now have to question that.

“On the other hand, we have identified potent inhibitors from our compound library that we can use as the starting point for identifying new candidates with the potential for developing drugs,” Olsen says.

The researchers based their study on extensive tests with the 11 human HDAC enzymes. The team developed chemically modified substrates for in vitro screening of enzymatic activity.

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This led to building an extensive library providing an overview of the enzymatic activities of HDACs against a variety of protein modifications in vitro. The researchers used their discovery to develop the first efficient assay for determining the efficacy of drugs against HDAC11 in vitro, which they say may become important for future development of drugs against diseases such as diabetes, cancer, inflammatory disease, and autoimmune disease.

Source: University of Copenhagen