GLP-1-directed NMDA receptor antagonism for obesity treatment

Jonas Petersen, Mette Q. Ludwig, Vaida Juozaityte, Pablo Ranea-Robles, Charlotte Svendsen, Eunsang Hwang, Amalie W. Kristensen, Nicole Fadahunsi, Jens Lund, Alberte W. Breum, Cecilie V. Mathiesen, Luisa Sachs, Roger Moreno-Justicia, Rebecca Rohlfs, James C. Ford, Jonathan D. Douros, Brian Finan, Bryan 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 and Christoffer Clemmensen ()
Additional contact information
Jonas Petersen: University of Copenhagen
Mette Q. Ludwig: University of Copenhagen
Vaida Juozaityte: University of Copenhagen
Pablo Ranea-Robles: University of Copenhagen
Charlotte Svendsen: University of Copenhagen
Eunsang Hwang: the University of Texas Southwestern Medical Center at Dallas
Amalie W. Kristensen: University of Copenhagen
Nicole Fadahunsi: University of Copenhagen
Jens Lund: University of Copenhagen
Alberte W. Breum: University of Copenhagen
Cecilie V. Mathiesen: University of Copenhagen
Luisa Sachs: University of Copenhagen
Roger Moreno-Justicia: University of Copenhagen
Rebecca Rohlfs: Novo Nordisk Research Center Indianapolis
James C. Ford: Novo Nordisk Research Center Indianapolis
Jonathan D. Douros: Novo Nordisk Research Center Indianapolis
Brian Finan: Novo Nordisk Research Center Indianapolis
Bryan Portillo: the University of Texas Southwestern Medical Center at Dallas
Kyle Grose: the University of Texas Southwestern Medical Center at Dallas
Jacob E. Petersen: University of Copenhagen
Mette Trauelsen: University of Copenhagen
Annette Feuchtinger: Helmholtz Munich
Richard D. DiMarchi: Indiana University
Thue W. Schwartz: University of Copenhagen
Atul S. Deshmukh: University of Copenhagen
Morten B. Thomsen: University of Copenhagen
Kristi A. Kohlmeier: University of Copenhagen
Kevin W. Williams: the University of Texas Southwestern Medical Center at Dallas
Tune H. Pers: University of Copenhagen
Bente Frølund: University of Copenhagen
Kristian Strømgaard: University of Copenhagen
Anders B. Klein: University of Copenhagen
Christoffer Clemmensen: University of Copenhagen

Nature, 2024, vol. 629, issue 8014, 1133-1141

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 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.

Date: 2024
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DOI: 10.1038/s41586-024-07419-8

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