The Scripps Research Institute has used a new drug screening platform to identify a drug which researchers believe has strong potential for treating diabetes.
Working with a technique dubbed autocrine selection, investigators are able to screen molecules in search of targets that can bind to and activate cellular receptors in order to achieve a sought-after drug effect.
In this latest study, published in Nature Communications, the Scripps team went after the GLP-1 receptor, which is already the target of a number of GLP-1 agonists. Scripps, though, wanted to activate the GLP-1 receptor's G protein pathway.
Hongkai Zhang focused on the GLP-1 agonist Extendin-4, whipping up a million peptides that could alter the end of the protein that activates the G protein and beta arrestin pathways.
"The idea was that at least one of these many variants would induce a change in the shape of the GLP-1 receptor that would activate the G-protein pathway without activating the beta arrestin pathway," Zhang said.
They then identified the one in a million that improved glucose tolerance at a radically reduced dose of Extendin-4, testing it on mice.
"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," said Emmanuel Sturchler, a staff scientist in the McDonald laboratory and co-first author of the study.