Current pharmacological therapies that target single receptors have limited efficacy for the treatment of diabetes and obesity. Novel approaches with hybrid peptides that activate more than one receptor at once to generate beneficial effects through synergistic effects have shown promising results. Several unimolecular dual and tri-agonists, mainly associated with GPCR like GLP-1/GCG/GIP receptors, have shown exceptional efficacy in preclinical models, and are currently being evaluated in clinical trials to investigate their safety and beneficial effects in humans. Areas covered: Herein, the authors review the development of drugs used in the treatment of metabolic disease, from single agonists to the new generation of tri-agonist peptides and compile the latest knowledge available on GPCR-based drug discovery. The authors also provide the reader with their expert perspectives on this exciting area of drug development. Expert opinion: The co-agonists that have been clinically tested so far have been well tolerated and reduce body weight as well as fasting glucose levels in patients with Type 2 Diabetes Mellitus to a higher degree than single agonists alone. The promising data collected so far now warrant large scale randomized clinical trials to assess whether a unimolecular polypharmacy-based approach could translate into safe and efficacious treatments for obesity and its comorbidities.
Keywords: GIP; GLP-1; GPCRs; T2DM; glucagon; obesity; unimolecular polypharmacy.