The study, “Anti-diabetic actions of non-agonist PPARy ligand blocking Cdk5-mediated phosphorylation,” appears in the international science weekly’s September 4 online edition. It describes a new class of compounds designed to target the nuclear receptor that contributes to obesity, peroxisome proliferator-activated receptor γ (PPARy), without the serious side effects that accompany many of the current drugs that target PPARy.
The CCS’s Stephan Schürer, Ph.D., research assistant professor of molecular and cellular pharmacology and the center’s lead scientist for chemoinformatics, and Dušica Vidović, Ph.D., associate scientist, contributed to the study by conducting the computational molecular modeling studies that predicted the binding mode of a new synthetic PPARy ligand.
“Importantly, this work demonstrates how PPARy-mediated gene expression and functional responses can be switched via small molecules that bind to the receptor,’’ Schürer said. “Using optimized small molecules, it is possible to modulate the receptor in very subtle ways and this response can be related to a specific binding mode – in this case to achieve antidiabetic efficacy while avoiding receptor activation and thus a number of serious side effects.”
Required for the accumulation of adipose tissue, or fat, PPARy activation contributes to obesity, but it also results in increased insulin sensitivity. This is the mechanism of the thiazolidinedione (TZD) class of antidiabetes drugs, including rosiglitazone and pioglitazone. However, TZD drugs, in use since the late 1990s, come with serious side effects, including fluid retention and weight gain.
In the study, using cultured cells and mice, the researchers describe novel synthetic compounds that have a unique mode of binding to PPARy and blocking the Cdk5 kinase-mediated phosphorylation of the receptor, which is involved in the pathogenesis of insulin resistance. One such compound, SR1664, proved to have potent antidiabetic activity without causing fluid retention and weight gain.
Unlike TZDs, the authors noted, SR1664 also does not interfere with bone formation in culture.
“These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPAR_γ_,’’ the researchers concluded.
The study was conceived and designed by Bruce M. Spiegelman, Ph.D., professor of cell biology at Harvard, and Patrick R. Griffin, Ph.D., professor and chair of the department of molecular therapeutics in the Scripps Florida Division of Drug Discovery, and in addition to UM’s Schürer and Vidović, included 16 other authors.