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. PetersenMette 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*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

19 Citations (Scopus)
59 Downloads (Pure)

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.

Original languageEnglish
JournalNature
Volume629
Issue number8014
Pages (from-to)1133–1141
ISSN0028-0836
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Cite this