PXD045816-1

PXD045816 is an original dataset announced via ProteomeXchange.

Title	GLP-1 directed NMDA receptor antagonism for obesity treatment
Description	The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.
HostingRepository	PRIDE
AnnounceDate	2024-04-26
AnnouncementXML	Submission_2024-04-26_03:59:00.439.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Roger Moreno Justicia
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-29 08:13:49	ID requested
⏵ 1	2024-04-26 03:59:01	announced

10.1038/S41586-024-07419-8;

submitter keyword: hypothalamus,GLP-1, obesity

Atul Deshmukh
contact affiliation	Novo Nordisk Foundation Center for Basic Metabolic Research
contact email	atul.deshmukh@sund.ku.dk
lab head
Roger Moreno Justicia
contact affiliation	Novo Nordisk Foundation Center for Basic Metabolic Research
contact email	roger.moreno.justicia@sund.ku.dk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/04/PXD045816

PRIDE project URI

• PRIDE
  1. PXD045816
     1. Label: PRIDE project
     2. Name: GLP-1 directed NMDA receptor antagonism for obesity treatment