GLP-1-directed NMDA receptor antagonism for obesity treatment

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  • Mette Q. Ludwig
  • Charlotte Svendsen
  • Eunsang Hwang
  • Amalie W. Kristensen
  • Nicole Fadahunsi
  • Luisa Sachs
  • Rebecca Rohlfs
  • James C. Ford
  • Jonathan D. Douros
  • Brian Finan
  • Bryan Portillo
  • Kyle Grose
  • Annette Feuchtinger
  • Richard D. DiMarchi
  • Kevin W. Williams
  • Anders B. Klein

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.

Udgave nummer8014
Sider (fra-til)1133–1141
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank H. Liu and P. Mehrwarz for experimental and technical assistance; L. L. Larsen, C. Zhang, U. Roostalu, A. N. Madsen, T. Porsgaard, N. Sonne and D. Dencker Thorbek for technical support; the previous and current members of the Clemmensen Group for technical assistance and scientific discussions; the staff at the Single-Cell Omics platform and the Rodent Metabolic Phenotyping Platform at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) for technical expertise and support; and the staff at the Biophysics Platform, Protein Structure and Function Program from The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen for performing the human serum albumin SPR binding measurements. Cartoon images were created using BioRender. This work was supported by the Lundbeck Foundation (fellowship R238-2016-2859), the BioInnovation Institute (grant number NNF20OC0063538) and the Novo Nordisk Foundation (grant numbers NNF17OC0026114 and NNF22OC0073778); and grants to E.H. (National Research Foundation of Korea, NRF 2021R1A6A3A14044733) and K.W.W. (R01 DK119169 and DK119130\u20135830). MS analyses were performed by the Proteomics Research Infrastructure (PRI) at the University of Copenhagen (UCPH), supported by the Novo Nordisk Foundation (NNF) (grant number NNF19SA0059305). Blood pressure recordings were performed by the Telemetry Unit for Cardiovascular Phenotyping at the University of Copenhagen, supported by the Novo Nordisk Foundation (grant number NNF18OC0032728 to M.B.T.). The Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (grant number NNF14CC0001). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, Denmark, and is partially funded by an unconditional donation from the Novo Nordisk Foundation ( ) (grant numbers NNF18CC0034900 and NNF23SA0084103).

Publisher Copyright:
© The Author(s) 2024.

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