PXD030336-1

PXD030336 is an original dataset announced via ProteomeXchange.

Title	The nitrobenzoxadiazole derivative NBDHEX behaves as Plasmodium falciparum gametocyte selective inhibitor with malaria parasite transmission blocking activity
Description	This work describes the activity of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and of its newly identified carboxylic acid metabolite on human malaria parasite Plasmodium falciparum. NBDHEX has been previously identified as a potent cytotoxic agent against murine and human cancer cells as well as towards the protozoan parasite Giardia duodenalis. We show here that NBDHEX is active in vitro against all blood stages of P. falciparum, with the rare feature of killing the parasite stages transmissible to mosquito, the immature and the mature gametocytes, with a 4-fold higher activity than that on the pathogenic asexual stages. This activity importantly translates into blocking parasite transmission through the Anopheles vector in mosquito experimental infections. A mass spectrometry analysis identified covalent NBDHEX modifications in specific cysteine residues of five gametocyte proteins, possibly associated to its antiparasitic effect. The carboxylic acid metabolite of NBDHEX retains the gametocyte preferential inhibitory activity of the parent compound, making this novel P. falciparum transmission blocking chemotype at least as a new tool to uncover biological processes targetable by gametocyte selective drugs. Both NBDHEX and its carboxylic acid metabolite show very limited in vitro cytotoxicity on VERO cells. This result and previous evidence that NBDHEX shows an excellent in vivo safety profile in mice and is orally active against human cancer xenografts make these molecules potential starting points to develop new P. falciparum transmission blocking agents, enriching the repertoire of drugs needed to eliminate malaria.
HostingRepository	PRIDE
AnnounceDate	2022-03-03
AnnouncementXML	Submission_2022-03-02_23:36:50.392.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marialuisa Casella
SpeciesList	scientific name: Plasmodium falciparum; NCBI TaxID: 5833; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-12 14:07:13	ID requested
⏵ 1	2022-03-02 23:36:50	announced
2	2023-11-14 08:54:12	announced	2023-11-14: Updated project metadata.

10.3390/PH15020168;

submitter keyword: Malaria

Plasmodium falciparum transmission

NBDHEX

mass spectrometry

Marialuisa Casella
contact affiliation	Italian NationalInstitute of Health
contact email	marialuisa.casella@iss.it
lab head
Marialuisa Casella
contact affiliation	Istituto Superiore di Sanità
contact email	marialuisa.casella@iss.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030336
     1. Label: PRIDE project
     2. Name: The nitrobenzoxadiazole derivative NBDHEX behaves as Plasmodium falciparum gametocyte selective inhibitor with malaria parasite transmission blocking activity