TY - JOUR
T1 - GLP-1-directed NMDA receptor antagonism for obesity treatment
AU - Petersen, Jonas
AU - Ludwig, Mette Q.
AU - Juozaityte, Vaida
AU - Ranea-Robles, Pablo
AU - Svendsen, Charlotte
AU - Hwang, Eunsang
AU - Kristensen, Amalie W.
AU - Fadahunsi, Nicole
AU - Lund, Jens
AU - Breum, Alberte W.
AU - Mathiesen, Cecilie V.
AU - Sachs, Luisa
AU - Moreno-Justicia, Roger
AU - Rohlfs, Rebecca
AU - Ford, James C.
AU - Douros, Jonathan D.
AU - Finan, Brian
AU - Portillo, Bryan
AU - Grose, Kyle
AU - Petersen, Jacob E.
AU - Trauelsen, Mette
AU - Feuchtinger, Annette
AU - DiMarchi, Richard D.
AU - Schwartz, Thue W.
AU - Deshmukh, Atul S.
AU - Thomsen, Morten B.
AU - Kohlmeier, Kristi A.
AU - Williams, Kevin W.
AU - Pers, Tune H.
AU - Frølund, Bente
AU - Strømgaard, Kristian
AU - Klein, Anders B.
AU - Clemmensen, Christoffer
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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 homeostasis1. 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.
AB - 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 homeostasis1. 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.
U2 - 10.1038/s41586-024-07419-8
DO - 10.1038/s41586-024-07419-8
M3 - Journal article
C2 - 38750368
AN - SCOPUS:85192940391
VL - 629
SP - 1133
EP - 1141
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 8014
ER -