A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents (original) (raw)

Obesity and its comorbidities, including type 2 diabetes, represent a global health threat and a rapidly increasing burden to economic prosperity 1. Therapeutic intervention is urgently required because lifestyle modification has proven mostly ineffective. Despite this vast unmet need, potent and safe pharmacological options that effectively promote weight loss and improve metabolic health have largely remained elusive 2 , partly because many drug interventions historically directed at single molecular targets have exhibited insufficient efficacy or unacceptable safety when used chronically 3. However, new multimolecular therapies have shown enhanced clinical weight loss 4-6 , and singlemolecule peptides integrating the complementary actions of multiple endogenous metabolically-related hormones have emerged as one of the more promising clinical candidates for reversing obesity 7-13. We sought to explore the synergistic metabolic benefits of simultaneous modulation of glucagon, GLP-1 and GIP receptors through a single-molecule hybrid of the three hormones. Glucagon, GLP-1 and GIP are three distinct enteroinsular hormones with unique roles that complement, as well as oppose, each other in the regulation of energy and glucose homeostasis 14-16. Previously, we reported the ability to assemble balanced, high-potency coagonism for the GLP-1 and glucagon receptors (GLP-1R and GcgR, respectively) into a single peptide 8. This peptide exhibited a synergistic ability to lower body weight through coordinated thermogenic and anorectic actions, which can be attributed to the glucagon and GLP-1 components, respectively. Simultaneously, we discovered a high-potency, balanced coagonist for the GLP-1R and GIP receptors (GIPR) 9. This dual incretin coagonist displayed enhanced glycemic efficacy, diminished gastrointestinal toxicity and reduced body weight in preclinical studies, as well as the ability to lower hemoglobin A1C in humans with uncontrolled type 2 diabetes 9. Having established the unique efficacy of these two coagonists with glucagon and GIP independently complementing GLP-1 by different mechanisms, we hypothesized that, if chemically possible, simultaneous and aligned agonism at all three receptors through a single molecule would produce superior therapeutic outcomes. All three hormones are of comparable size and amino acid composition but sufficiently distinct to provide exquisite potency and specificity