Authors: Jillian L. Seiler, Anna C. Impastato, Emma (Xiaoyu) Zhang, Kade J. Kelley, Thomas L. Bennett, Bradley Studnitzer, Claudia R. Prindle, Benjamin H. Rajewski, Barry A. Badeau, Xinjian Jiang, Russell Potterfield, Jordan Y. Delev, Daniel L. Marks
Abstract:
The melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists has prompted investigation into whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation may more effectively engage this pathway for the treatment of general obesity. Here we show that selective MC3R agonism modulates food intake in a state-dependent manner, and that co-agonism of MC3R and MC4R produces greater metabolic effects than selective MC4R agonism alone, consistent with non-redundant and cooperative roles. Using novel peptides in male nonhuman primates and rodents, we develop 710GO, an orally available MC3R/MC4R dual agonist that induces significant weight loss in primates with diet-induced obesity. Oral 710GO demonstrates limited weight rebound, compatibility with GLP-1–based therapies, and a favorable preclinical safety profile. These findings support combined MC3R/MC4R agonism as a promising approach for next-generation obesity therapeutics.