PXD058545-1

PXD058545 is an original dataset announced via ProteomeXchange.

Title	GRK-biased adrenergic agonists for the treatment of type II diabetes and obesity
Description	Biased agonism of G protein-coupled receptors (GPCRs) holds great promise for the development of safer medications. Current efforts have explored the balance between heterotrimeric G proteins and the scaffold protein b-arrestin; however, other transducers like GPCR kinases (GRKs) represent important, but understudied mediators of agonist-induced signaling. In particular, GRK2 has been shown to play an essential role in b2 adrenergic receptor (b2AR)-mediated glucose uptake, but b2AR agonists are generally thought to make poor clinical candidates for glycemic management given their potential for Gs/cAMP-induced cardiac side effects and tendency for b-arrestin-dependent desensitization with long-term treatment. For these reasons, we sought to develop pathway-selective agonists of b2AR that prefer GRK coupling to heterotrimeric Gs and b-arrestin. Ligand-based virtual screening and chemical evolution of adrenergic agonists led to the identification of GRK-biased b2AR partial agonists. We demonstrate that these compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared to standard b2-receptor agonists and incretin mimetics respectively. Furthermore, our lead candidate showed favorable pharmacokinetics and was determined to be safe in a placebo-controlled clinical trial. GRK-biased b2AR partial agonists are thus promising candidates to offer a viable, orally available alternative to injection-based incretin mimetics used in the treatment of type II diabetes and obesity.
HostingRepository	PRIDE
AnnounceDate	2025-05-05
AnnouncementXML	Submission_2025-05-05_01:05:35.659.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pierre Sabatier
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-03 16:36:48	ID requested
⏵ 1	2025-05-05 01:05:36	announced

Dataset with its publication pending

submitter keyword: b2AR,Phosphoproteomics, obesity, GRK2, diabetes

Jesper Velgaard Olsen
contact affiliation	Novo Nordisk Foundation Center for Protein Research
contact email	jesper.Olsen@cpr.ku.dk
lab head
Pierre Sabatier
contact affiliation	Department of Surgical Sciences, Uppsala University. Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
contact email	pierre63.sabatier@gmail.com
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/2025/05/PXD058545

PRIDE project URI

• PRIDE
  1. PXD058545
     1. Label: PRIDE project
     2. Name: GRK-biased adrenergic agonists for the treatment of type II diabetes and obesity