Dataset Information

WEHI991 drug target identification by DIA Solvent PISA

ABSTRACT: Here we demonstrate PfSTART1 engagement by WEHI991 in the P. falciparum proteome using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assay coupled with Data Independent Acquisition Mass Spectrometry (DIA-MS).

ORGANISM(S): Plasmodium (plasmodium)

SUBMITTER: Jerzy Dziekan

PROVIDER: PXD048262 | JPOST Repository | Wed May 01 00:00:00 BST 2024

REPOSITORIES: jPOST

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20230825_P4515_G1R1_1.raw	Raw
	20230825_P4515_G1R1_4.raw	Raw
	20230825_P4515_G1R2_1.raw	Raw
	20230825_P4515_G1R2_4.raw	Raw
	20230825_P4515_G1R3_1.raw	Raw

Items per page:

1 - 5 of 13

Publications

Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1.

Dans Madeline G MG Boulet Coralie C Watson Gabrielle M GM Nguyen William W Dziekan Jerzy M JM Evelyn Cindy C Reaksudsan Kitsanapong K Mehra Somya S Razook Zahra Z Geoghegan Niall D ND Mlodzianoski Michael J MJ Goodman Christopher Dean CD Ling Dawson B DB Jonsdottir Thorey K TK Tong Joshua J Famodimu Mufuliat Toyin MT Kristan Mojca M Pollard Harry H Stewart Lindsay B LB Brandner-Garrod Luke L Sutherland Colin J CJ Delves Michael J MJ McFadden Geoffrey I GI Barry Alyssa E AE Crabb Brendan S BS de Koning-Ward Tania F TF Rogers Kelly L KL Cowman Alan F AF Tham Wai-Hong WH Sleebs Brad E BE Gilson Paul R PR

Nature communications 20240618 1

With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTAR ...[more]

PMID: 38890312

Similar Datasets

Project description:Malaria remains a global health threat, with rising drug resistance accelerating the urgent need for new therapeutics. Target elucidation is a critical step in antimalarial drug discovery, enabling a deeper understanding of the molecular mechanisms of action of both existing and novel compounds. This study validates solvent-induced proteome profiling (SPP) as a proteomics-based approach for identifying drug-protein interactions in Plasmodium falciparum. SPP de-tects shifts in protein stability induced by ligand binding, allowing the identification of drug target/s without the need for compound modifications. Here, we successfully generated solvent denaturation curves for the P. falciparum pro-teome, and demonstrated the utility of SPP with five antimalarial compounds: pyrimethamine, atovaquone, cipar-gamin, MMV1557817 and OSM-S-106. In addition to measuring each compound’s impact across the full denatura-tion curve, investigating protein levels at individual solvent percentages preserved specific stability changes that would otherwise be masked in pooled analyses performed by integral SPP. This strategy was critical for the identifi-cation of the cipargamin target, non-SERCA-type Ca2+-transporting P-ATPase (PfATP4). Notably, we propose live-cell treatment SPP as a novel approach, demonstrating its ability to identify the validated target of pyrimethamine, bifunctional dihydrofolate reductase-thymidylate synthase (PfDHFR), with high specificity. We also introduced the novel one-pot mixed-drug SPP, which enables the evaluation of multiple drugs within a single lysate and experi-mental setup. This alternative method simplifies the experimental workflow and includes positive controls to affirm the performance of the experiment. Overall, this study demonstrates that SPP can be successfully applied in both ly-sate and live-cell treatment conditions to elucidate drug targets in P. falciparum, as well as providing additional in-formation regarding the mechanisms of drug action, offering insights for the optimisation of existing antimalarials and the development of novel therapies.