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Petersen, J.* ; Ludwig, M.Q.* ; Juozaityte, V.* ; Ranea-Robles, P.* ; Svendsen, C.* ; Hwang, E.* ; Kristensen, A.W.* ; Fadahunsi, N.* ; Lund, J.* ; Breum, A.W.* ; Mathiesen, C.V.* ; Sachs, L.* ; Moreno-Justicia, R.* ; Rohlfs, R.* ; Ford, J.C.* ; Douros, J.D.* ; Finan, B.* ; Portillo, B.* ; Grose, K.* ; Petersen, J.E.* ; Trauelsen, M.* ; Feuchtinger, A. ; DiMarchi, R.D.* ; Schwartz, T.W.* ; Deshmukh, A.S.* ; Thomsen, M.B.* ; Kohlmeier, K.A.* ; Williams, K.W.* ; Pers, T.H.* ; Frølund, B.* ; Strømgaard, K.* ; Klein, A.B.* ; Clemmensen, C.*

GLP-1-directed NMDA receptor antagonism for obesity treatment.

Nature 629, 1133-1141 (2024)

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	Open Access Gold (Paid Option)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Body-temperature; Food-intake; Mk-801; Memantine; Weight; Activation; Tolerance; Reverses; Neurons

ISSN (print) / ISBN 0028-0836

e-ISSN 1476-4687

Journal Nature

Quellenangaben Volume: 629, Issue: 8014, Pages: 1133-1141

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CF Pathology & Tissue Analytics (CF-PTA)

Grants Novo Nordisk Foundation Center for Basic Metabolic Research
BioInnovation Institute
Novo Nordisk Foundation
National Research Foundation of Korea, NRF
Novo Nordisk Foundation (NNF)
Novo Nordisk Foundation Center for Protein Research
Lundbeck Foundation