PXD079493-1

PXD079493 is an original dataset announced via ProteomeXchange.

Title	Chemoproteomic profiling of Plasmodium falciparum Hsp90 inhibition reveals functional link to DNA replication pathways
Description	Heat shock protein 90 (Hsp90) plays a critical role in maintaining the proteostasis of Plasmodium falciparum, the most lethal malaria parasite. Although PfHsp90 is recognized as a promising antimalarial target, its interactome and the global proteomic remodeling induced by its inhibition remain poorly characterized. Herein, we leveraged global chemoproteomic profiling employing two PfHsp90 inhibitors with distinct scaffolds, geldanamycin and XL888, to investigate proteins and pathways dependent on the chaperone during the P. falciparum asexual blood stage. This study revealed 133 hits with significantly decreased abundances in response to PfHsp90 inhibition with both compounds. A subset of these hits demonstrated conservation as Hsp90 interactors in yeast and human model organisms, while a large majority of the hits lacked predicted orthologs. Bioinformatics analyses of the hits yielded strong enrichment in DNA replication and associated processes and this link was confirmed in phenotypic studies demonstrating that PfHsp90 inhibition reduces the total P. falciparum DNA content. To specifically assess nascent DNA synthesis, we utilized a 7-deaza-7-ethynyl-2’-deoxyadenosine (EdA) incorporation assay, which demonstrated impairment of active DNA replication following PfHsp90 inhibitor treatment. We further show that the co-treatment of parasites with PfHsp90 and DNA replication inhibitors produces synergistic interactions, highlighting the therapeutic potential of the discovered link. Together these findings reveal over a hundred putative Hsp90-dependent proteins as possible interactors in the pathogenic parasites, where the functional dependence of P. falciparum DNA replication on PfHsp90 was validated. These efforts expand our understanding of PfHsp90 function and uncover the potential for dual targeting of these pathways in the fight against malaria.
HostingRepository	PRIDE
AnnounceDate	2026-08-28
AnnouncementXML	Submission_2026-08-28_07:44:52.911.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yueqi Chen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Plasmodium falciparum (isolate 3D7); NCBI TaxID: NEWT:36329;
ModificationList	methylthiolated residue; acetylated residue; monohydroxylated residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2026-06-09 20:29:25	ID requested
⏵ 1	2026-08-28 07:44:53	announced

Dataset with its publication pending

submitter keyword: Heat shock protein 90

Hsp90

Plasmodium

chemoproteomics

synergy

Michael C. Fitzgerald
contact affiliation	Chemistry department, Duke university
contact email	michael.c.fitzgerald@duke.edu
lab head
Yueqi Chen
contact affiliation	Duke University
contact email	yc469@duke.edu
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/2026/08/PXD079493

PRIDE project URI

• PRIDE
  1. PXD079493
     1. Label: PRIDE project
     2. Name: Chemoproteomic profiling of Plasmodium falciparum Hsp90 inhibition reveals functional link to DNA replication pathways