Research Overview
The Melanocortin Receptors
Our group has dedicated a significant portion of our research efforts to the Melanocortin receptors, a family of G Protein-Coupled Receptors (GPCRs). Of particular interest are the roles of the centrally expressed melanocortin-3 and –4 receptors (MC3R & MC4R) in fat storage and food intake. Agonists for the MC3R and MC4R have been demonstrated to decrease food intake while antagonist ligands have been shown to increase intake. Using a variety of methodologies, our lab makes potent, selective ligands for this GPCR family to characterize the roles of the different receptor subtypes.
There is extensive history in the field focused on the identification and manipulation of endogenous ligands for the Melanocortin receptors to better understand their role and function in human physiology. We leverage solid-phase peptide synthesis (SPPS) to expand upon these known natural peptides to unlock more potent and selective ligands. In addition, our group uses an unbiased method to actively explore novel chemical space through a collaboration with Florida International University that utilizes mixture-based combinatorial libraries to efficiently sample millions of peptide-like small molecules for characterization at the Melanocortin receptors. You can read more about those library screening efforts and other synthetic projects on our Organic & Medicinal Chemistry page.
We utilize a variety of in vitro cell-based assays to help us screen and characterize novel ligands. Within our group, we have the ability to monitor intracellular cyclic AMP (cAMP) levels through the use of orthogonal assays, in addition to β-arrestin signaling, Ca2+ flux, radioactive ligand binding, and more. We're constantly incorporating new methodologies from the literature to better support our work. You can read more about the assays we use on our GPCR Molecular Pharmacology page.
After successfully characterized novel ligands with in vitro assays, we assess the physiological impact of these compounds in live animal models to ensure safety and effectiveness. The Haskell-Luevano lab has mice with special genetic mutations that knock out the MC3R and/or MC4R, which allows us to effectively model human metabolic diseases like obesity and Type II Diabetes. The use of these animals helps us examine how the Melanocortins receptors directly impact metabolism. You can read more about our animal models and research on our in vivo studies page.