PXD051499

PXD051499 is an original dataset announced via ProteomeXchange.

Title	Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets
Description	Malaria, caused by Plasmodium falciparum, remains a significant health burden. The barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that Salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism with a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent anti-parasitic potencies which enabled the identification of therapeutically relevant targets. We also confirm that this compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor, Orlistat. In addition, like SalA, our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:50:02.661.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Daniel Abegg
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Plasmodium falciparum (isolate 3D7); NCBI TaxID: 36329;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-16 12:01:48	ID requested
1	2024-07-15 13:48:26	announced
⏵ 2	2024-10-22 06:50:03	announced	2024-10-22: Updated project metadata.

10.1101/2024.01.11.575224;

Bennett JM, Narwal SK, Kabeche S, Abegg D, Hackett F, Yeo T, Li VL, Muir RK, Faucher FF, Lovell S, Blackman MJ, Adibekian A, Yeh E, Fidock DA, Bogyo M, Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets. bioRxiv, ():(2024) [pubmed]

submitter keyword: Plasmodium, lipid metabolism, serine hydrolases, activity-based probes

Alexander Adibekian
contact affiliation	Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA
contact email	dabegg@uic.edu
lab head
Daniel Abegg
contact affiliation	University of Illinois at Chicago
contact email	dabegg@uic.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/2024/07/PXD051499

PRIDE project URI

• PRIDE
  1. PXD051499
     1. Label: PRIDE project
     2. Name: Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets