Scientists have found a new anti-diabetes compound using a powerful new technique for discovering drugs, according to The Scripps Research Institute (TSRI).
They said the technique known as "autocrine selection" involved taking a library of slightly altered molecules based on a protein, Exendin-4, originally found in the venom of Gila Monster lizards.
“In principle, we can apply this technique to hundreds of other receptors like the one we targeted in this study to find disease treatments that are more potent and have fewer side effects than existing therapies," said Patricia H. McDonald, an assistant professor at TSRI’s Jupiter, Florida campus and a senior investigator of the study.
"It has been a very productive cross-campus collaboration, so we’re hoping to build on its success as we continue to collaborate on interrogating potential therapeutic targets."
The institute said that a senior staff scientist at the Richard A. Lerner's laboratory, Hongkai Zhang, created about one million new peptides by randomly varying one end of Exendin-4.
Their research aimed to find new way to activate the GLP-1 receptor, which creates insulin-producing "beta cells" in the pancreas, said the institute. There are already several drugs that achieve this purpose.
However, the team wanted to find a molecule that only activates a single chain of biochemical signals within the beta cell. Previous drug treatments have used molecules that activated multiple pathways of signals, which scientists have recently realized may not be as effective as only stimulating one distinct pathway, according to the institute.
After Zhang created a huge library of peptides from Exendin-4, he eventually isolated one known as P5, that selectively activated a specific G-protein pathway. The institute said an initial study of mice demonstrated the P5 could successfully boost glucose tolerance, at a more effective rate than previous diabetes medications have.
According to the institute, the peptide only stimulates insulin production weakly and it actually triggers the growth of new fat cells. In obesity-related diabetes, fat cells often grow large enough that they develop insulin resistance. P5 helps to alleviate insulin resistance by helping the body develop fat cells that are more sensitive to insulin.
“We didn’t expect that, but in fact, it was a nice finding because less reliance on stimulating insulin could mean less stress on the beta cells,” said Emmanuel Sturchler, staff scientist in the McDonald laboratory and co-first author of the study.
McDonald's laboratory worked with Lerner's laboratory, the Lita Annenberg Hazen Professor of Immunochemistry at TSRI's La Jolla campus. Lerner is known for pioneering techniques that generate and screen large ammounts of proteins to develop new drug treatments.
“P5’s mechanisms of action turned out to be quite different from Exendin-4’s, and we think that this finding could lead to new therapeutics,” Sturchler said.
The institute said the team will now search for opportunities to create a new diabetes drug using P5.