PXD057395-1

PXD057395 is an original dataset announced via ProteomeXchange.

Title	A Phosphotriester-Masked Dideoxy-cGAMP Derivative as a Cell-Permeable STING Agonist
Description	2’3’-cyclic GMP-AMP (cGAMP) is a cyclic dinucleotide second messenger in which guanosine and adenosine are connected by one 3’-5’ and one 2’-5’ phosphodiester linkage. It is formed in the cytosol upon detection of pathogenic DNA by the enzyme guanosine-monophosphate-adenosine monophosphate synthase (cGAS). cGAMP subsequently binds to the adaptor protein stimulator of interferon genes (STING) to elicit an innate immune response leading to the production of type I interferons and cytokines. STING agonists are a highly promising avenue for an immuno-oncological anticancer therapy. A particular challenge with cyclic dinucleotide STING agonists are the two negative charges of the phosphodiester linkages, which strongly reduce the ability of such compounds to penetrate cell membranes. The development of cell-permeable STING agonists that can stimulate the immune system to enhance their anticancer potency is currently of utmost importance in the field. Here, we report the development of a dideoxy derivative of cGAMP as a phosphotriester prodrug, where the negative charge of the phosphate backbone has been masked with a thioester. We found that this thioester-protected compound features a dramatic increase in its cellular potency that rises from EC50 = 5 µM to 25 nM. The new compound is envisioned to enable an efficient STING-agonist-based anticancer therapy.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_04:28:54.962.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Markus Müller
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse; Thermo Fisher Scientific instrument model

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-31 07:00:22	ID requested
⏵ 1	2025-05-07 04:28:55	announced

10.1002/anie.202416353;

Halbritter AJ, G, ä, rtner YV, Nabiev J, Hernichel F, Ganazzoli G, Ö, zdemir D, Pappa A, Veth S, Stazzoni S, M, ü, ller M, Hornung V, Carell T, A Phosphotriester-Masked Dideoxy-cGAMP Derivative as a Cell-Permeable STING Agonist. Angew Chem Int Ed Engl, 63(52):e202416353(2024) [pubmed]

submitter keyword: STING, Interferone,cGAMP

Thomas Carell
contact affiliation	Ludwig-Maximilians Universität München Department Chemie Butenandtstr. 5-13 81377 München
contact email	thomas.carell@cup.lmu.de
lab head
Markus Müller
contact affiliation	Ludwig-Maximilians Universität München Department Chemie AK Carell Butenandtstr. 5-13 81377 München
contact email	markus.mueller@cup.lmu.de
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/PXD057395

PRIDE project URI

• PRIDE
  1. PXD057395
     1. Label: PRIDE project
     2. Name: A Phosphotriester-Masked Dideoxy-cGAMP Derivative as a Cell-Permeable STING Agonist