GLP-1-directed NMDA receptor antagonism for obesity treatment
Jonas Petersen, Mette Q. Ludwig, Vaida Juozaityte, Pablo Ranea‐Robles, Charlotte Svendsen, Eun‐Sang Hwang, Amalie W Kristensen, Nicole Fadahunsi, Jens Lund, Alberte Wollesen Breum, Cecilie Vad Mathiesen, L. Sachs, Roger Moreno‐Justicia, Rebecca Rohlfs, James Ford, Jonathan D. Douros, Brian Finan, B Portillo, Kyle Grose, Jacob E. Petersen, Mette Trauelsen, Annette Feuchtinger, Richard D. DiMarchi, Thue W. Schwartz, Atul S. Deshmukh, Morten B. Thomsen, Kristi A. Kohlmeier, Kevin W. Williams, Tune H. Pers, Bente Frølund, Kristian Strømgaard, Anders B. Klein, Christoffer Clemmensen
Abstract
Abstract The N -methyl- d -aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis 1 . Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.