PXD046006-2

PXD046006 is an original dataset announced via ProteomeXchange.

Title	On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity
Description	To combat the global burden of malaria, development of new drugs to replace or complement current therapies are urgently required. As drug resistance to existing treatments and clinical failures continue to rise, compounds targeting multiple life cycle stages and species need to be developed as a high priority. Here we show that the compound MMV1557817 is a nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end stage haemoglobin digestion in asexual parasites. Multi-stage analysis confirmed that MMV1557817 can also kill sexual stage P. falciparum, while cross-resistance studies confirmed the compound targets a mechanism of action distinct to current drug resistance mechanisms. Analysis of cross reactivity to homologous human enzymes shows the compound exhibits a high level of selectivity, whilst safety as well as druggability was confirmed in the murine model P. berghei. MMV1557817-resistant P. falciparum parasites displayed only low-level resistance (<3-fold) and exhibited a slow growth rate that was quickly outcompeted by wild type parasites. MMV1557817-resistant parasites digest significantly more haemoglobin and possess a mutation in PfA-M17 that induces partial destabilization of the PfA-M17 homohexamer, resulting in high-level resistance to specific PfA-M17 inhibition, but enhanced sensitivity to specific PfA-M1 inhibition, and importantly, these parasites were highly sensitive to artemisinin. Overall, these results confirm MMV1557817 as a potential lead compound for further drug development and highlight the potential of dual inhibition of M1 and M17 as an effective multi-species drug targeting strategy.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:38:12.618.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ghizal Siddiqui
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-09 15:48:39	ID requested
1	2024-05-06 06:01:28	announced
⏵ 2	2024-10-22 06:38:13	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: malaria,antimalarial, plasmodium falciparum

Darren Creek
contact affiliation	Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
contact email	darren.creek@monash.edu
lab head
Ghizal Siddiqui
contact affiliation	Monash University
contact email	ghizal.siddiqui@monash.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046006
     1. Label: PRIDE project
     2. Name: On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity