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Novel Polypharmacological Options to Treat Obesity and Diabetes
The ever-growing prevalence of obesity and diabetes propel an increasing demand for drugs to control body weight. Historical weight-loss medication was often compromised by an unfavorable imbalance between efficacy and safety. However, hope is resting on recent advances in biochemical engineering of molecules which, through intermixed sequence hybridization, combine the beneficial effects of several in dependent hormones into a single entity of enhanced potency and sustained action. Since more than a decade we have now co-pioneered this concept of polypharmacology by designing and evaluating molecules with balanced simultaneous action on the receptors for GLP-1, GIP and glucagon. First reported by us in 2009, a series of these molecules are nowadays in clinical evaluation and recently first human data emerged demonstrating an unmet efficacy at tolerable doses relative to best-in-class FDA/EMA approved drugs. While the first dual-agonists are awaiting regular approval, we expanded this concept of polypharmacology by designing drugs that covently link nuclear acting hormones (such as estrogen, T3 or dexamethasone) to the peptide hormones GLP-1 or glucagon. The vison residing in this concept is that such peptide-nuclear hormone conjugate would be internalized at only its target cell and would thus restrict the nuclear hormone cargo to only enter and act on cells that express the peptide hormone receptor and in which the nuclear hormone has beneficial effects. As proof-of-principle, we reported the GLP-1 mediated delivery of estrogen to selected tissues relevant in systemic energy metabolism control. The tissue-specific delivery of estrogen maximized its beneficial effects on metabolism without oncogenic estrogen action in GLP-1R negative tissues. Expanding this concept of peptide-mediated nuclear hormone delivery, we also reported targeted delivery of the thyroid hormone T3 to the liver using glucagon as the peptide carrier and more recently the improvement of hypothalamic inflammation via targeted delivery of dexamethasone using GLP-1 as carrier. We now further expanded this concept to also drugs that target the pancreas to improve β-cell mass under conditions of type 1 diabetes and also to drugs that specifically target hypothalamic neurocircuitries to modulate food intake and energy metabolism. Collectively, this concept of unimolecular polypharmacology is seemingly lightening the path to a new era in weight loss pharmacology.