PXD036288

PXD036288 is an original dataset announced via ProteomeXchange.

Title	Drug-target of DNA methyltransferase inhibitors
Description	Malaria eradication requires the development of new drugs to combat drug-resistant parasites. The search for new chemical scaffolds that target novel pathways of the human malaria parasite Plasmodium falciparum is of highest priority. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus sp. (trilobine derivatives) as active in the nanomolar range against P. falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivates allowed us to identify compound 84 (c-84) that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35-88nM). Efforts were made to obtain compounds with significantly improved preclinical properties. Out of those, compound 125 (c-125) delays the onset of parasitemia in P. berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays) and in vivo using membrane feeding assay in the Anopheles stephensi vector. C-125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, we used a chemical pull-down to identify potential protein targets of this chemical family. Our mass spectrometry analysis identified the parasite interactome with trilobine alkaloid, allowing us to identify protein partners belonging to metabolic pathways that have not been previously targeted by antimalarial drugs or implicated in drug-resistance mechanisms in malaria parasites.
HostingRepository	PRIDE
AnnounceDate	2023-01-01
AnnouncementXML	Submission_2023-01-01_15:01:30.688.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	MARIETTEMATONDO
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Plasmodium falciparum (isolate 3D7); NCBI TaxID: 36329;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-25 14:25:55	ID requested
⏵ 1	2023-01-01 15:01:31	announced

Dataset with its publication pending

submitter keyword: plasmodium,Click Chemistry methyltransferase

NardellaFlore
contact affiliation	Biologie des interactions hôte-parasite Institut Pasteur
contact email	flore.nardella@pasteur.fr
lab head
MARIETTEMATONDO
contact affiliation	Pasteur
contact email	mariette.matondo@pasteur.fr
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/2023/01/PXD036288

PRIDE project URI

• PRIDE
  1. PXD036288
     1. Label: PRIDE project
     2. Name: Drug-target of DNA methyltransferase inhibitors