New Method of Stabilizing Peptides Opens Doors to Diabetes Treatment

Spring/Summer 2018

E. James Petersson, Associate Professor of Chemistry | Photo credt: Lisa Godfrey

For many people with advanced Type 2 diabetes, taking insulin is a regular part of their routine, helping them control their blood sugar by signaling the metabolism of glucose. But recently, researchers have been investigating GLP-1, a peptide that gets activated when people eat, triggering insulin through a more natural pathway.

“Proteins do a lot of the work in cells,” says E. James Petersson, Associate Professor of Chemistry. “Peptides are shorter, and they're not really functional as machines in the same way that proteins are. But what they can do is signal molecules. One cell will secrete a peptide, and it will travel through the bloodstream and activate another type of cell.”

The problem with giving patients GLP-1 to trigger insulin production is that the peptide degrades in about two minutes due to natural enzymes in the body that break it apart, a process called proteolysis. In a paper published in the Journal of the American Chemical Society and highlighted in Nature, Petersson’s team used in-vitro experiments and in-vivo studies in rats to demonstrate that, by modifying the peptide backbones, they can block interactions with the enzymes that degrade peptides and can produce a stabilized, longer-lasting version of the drug.

“Every amino acid in a peptide is connected by an amide bond,” Petersson says. “We've been working on modifying that carbon, oxygen, and nitrogen connection to a carbon, sulfur, and nitrogen connection, a thioamide. We wanted to test whether this could be useful in a therapeutic context, and so we picked GLP-1 because it’s been established that if you could stabilize it then it would be a valuable diabetes treatment.”

One important property of GLP-1 is that it’s not degraded everywhere throughout the peptide; there's one specific bond that breaks apart. The researchers knew that being able to stop that cleavage would give them a much more stable version of the drug, so they replaced the oxygen atom located at that bond with a sulfur atom. With just this single atom substitution, they were able to increase the half-life of the drug from two minutes to a span of 12 to 24 hours.

After performing in vitro tests of this method, Petersson struck up a collaboration with Matthew Hayes, Associate Professor of Nutritional Neuroscience in Psychiatry at the Perelman School of Medicine, to see if it could actually be used in vivo. They were able to show that, in rats, the peptide was indeed longer lived and more potent than the native GLP-1. They showed that the modified peptide was as much as 750 times more stable than the natural variety, giving rats smaller blood-sugar spikes after meals.

This new method, Petersson says, does a really nice job of stopping proteolysis while being a very small modification of the peptide. The fact that they can prevent degradation without affecting other aspects of the peptide is a key finding.

“This research shows what an amazing effect just a single atom change can have,” Petersson says. “We really need to think carefully about the chemical structure of the molecules. Understanding molecular interactions even down to single atom detail can be crucial in making valuable molecules for in-vivo studies. I think this method will allow us to learn something really interesting about fundamental biology, and our long-term plan is to apply it where all other ways to stabilize injectable peptides have failed.”

By Ali Sundermier