Researchers discovered a small molecule that inhibits an enzyme that degrades insulin.
Harvard researchers may have finally identified a chemical compound that could be used to study and treat diabetes after decades of searching. They have discovered a whole different method for maintaining insulin in the blood: by blocking the enzyme that breaks it down.
Researchers have long known that the body carries an enzyme that breaks down insulin inside cells and helps regulate the body’s response to sugars—a process that goes awry in type 2 diabetes. Genetic studies have shown that people with type 2 diabetes are more likely to have mutations in the gene that encodes a protein called insulin-degrading enzyme, or IDE. But exactly which processes the enzyme controls is not yet clear.
David Liu and his team at Harvard have identified a chemical compound that can inhibit IDE, and they have shown that the compound increases the amount of insulin in the bloodstreams of both normal mice and ones made obese by an unhealthy diet.
Liu and his team developed the new compound using a novel method called DNA-templated synthesis. This involves linking thousands of different chemical structures to thousands of unique DNA strands, and then taking advantage of the interactions between two strands of DNA to bring the chemical building blocks together to create new ones.
Patients with type 2 diabetes either have an insufficient amount of insulin in their blood or do not properly respond to the hormone in order to move the body’s main energy source—glucose—into cells. Researchers have speculated for decades that a drug that could inhibit IDE might help some type 2 diabetes patients.
Small-molecule drugs, which make up the majority of medicines, are compounds far smaller than less common biological medicines like antibodies. They are developed using libraries of thousands or millions of known chemical substances. Each compound is screened to see if it has a desired effect on a biological target, such as an enzyme or other protein known to be involved in a disease. Pharmaceutical companies may use robotics to test many chemical reactions in parallel.
DNA-templated synthesis allows researchers without a lot of expensive equipment to more quickly evaluate all the potential small molecule interactions that could occur from a library of building blocks. “A single student with only minimal equipment and infrastructure can evaluate millions of potential small molecule-protein interactions in one to two weeks,” says Liu.
Furthermore, DNA-templated synthesis can produce structures that are often not found in chemical libraries used by many pharmaceutical companies, which may be why the Harvard team was able to identify an IDE-controlling drug when so many had failed in the past.
The newly identified IDE inhibitor could be the starting point for developing a powerful new drug for type 2 diabetes. Another compound was previously known to inhibit IDE, but it had unwanted side effects, and it survived for only a few minutes in the body. The new inhibitor lasts for hours, says Liu.
Photo credit: Sprichie