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Target identification of an antimalarial oxaborole identifies AN13762 as an alternative chemotype for targeting CPSF3 in apicomplexan parasites.

ABSTRACT: Target identification of an antimalarial oxaborole identifies AN13762 as an alternative chemotype for targeting CPSF3 in apicomplexan parasites.

PROVIDER: PRJNA658697 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12495651_1.fastq.gz	Fastqsanger.gz
	SRR12495651_2.fastq.gz	Fastqsanger.gz
	SRR12495652_1.fastq.gz	Fastqsanger.gz
	SRR12495652_2.fastq.gz	Fastqsanger.gz
	SRR12495653_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Target identification of an antimalarial oxaborole identifies AN13762 as an alternative chemotype for targeting CPSF3 in apicomplexan parasites.

Project description:Purpose: To shed light on the parasiticidal mechanisms of AN13762, we have adapted an original workflow which combines a forward genetic approach based on transcriptome sequencing, computational mutation discovery and CRISPR/Cas9 genome editing in Toxoplasma gondii. Drug-resistant parasites were generated by chemical random mutagenesis. Multiple independent resistant lines were isolated. Single nucleotide variations (SNVs) were identified based on NGS transcriptomic analysis. By focusing on mutations present in coding sequences, we identified a single gene, TgCPSF3, that harbored SNVs leading to amino acid substitutions in each of the 7 drug-resistant lines that were not present in the parental strain. Finally, using CRISPR/Cas9 genome editing we confirmed that the mutations identified confer resistance against AN13762.

2020-11-30 | GSE156685 | GEO

Identification of antimalarial compounds that inhibit Apicomplexan AP2 transcription factor proteins in the human malaria parasite Plasmodium falciparum [ChIP-seq]

Project description:Plasmodium parasites are reliant on the Apicomplexan AP2 (ApiAP2) transcription factor family to regulate gene expression programs. AP2 DNA binding domains have no homologs in the human or mosquito host genomes, making them potential antimalarial drug targets. Using an in-silico screen to dock thousands of small molecules into the crystal structure of the AP2-EXP (Pf3D7_1466400) AP2 domain (PDB:3IGM), we identified compounds that interact with this domain. Four compounds were found to compete for DNA binding with AP2-EXP and at least one additional ApiAP2 protein. Our top ApiAP2 competitor compound perturbs the transcriptome of P. falciparum trophozoites and results in a decrease in abundance of log2 fold change > 2 for 50% (46/93) of AP2-EXP target genes. Additionally, two ApiAP2 competitor compounds have multi-stage anti-Plasmodium activity against blood and mosquito stage parasites. In summary, we describe a novel set of antimalarial compounds that are targeted against the ApiAP2 family of proteins. These compounds may be used for future chemical genetic interrogation of ApiAP2 proteins or serve as starting points for a new class of antimalarial therapeutics.

2022-07-15 | GSE208155 | GEO

Target Identification of an Antimalarial Oxaborole Identifies AN13762 as an Alternative Chemotype for Targeting CPSF3 in Apicomplexan Parasites.

Project description:Boron-containing compounds represent a promising class of molecules with proven efficacy against a wide range of pathogens, including apicomplexan parasites. Following lead optimization, the benzoxaborole AN13762 was identified as a preclinical candidate against the human malaria parasite, yet the molecular target remained uncertain. Here, we uncovered the parasiticidal mechanisms of AN13762, by combining forward genetics with transcriptome sequencing and computational mutation discovery and using Toxoplasma gondii as a relevant model for Apicomplexa. AN13762 was shown to target TgCPSF3, the catalytic subunit of the pre-mRNA cleavage and polyadenylation complex, as the anti-pan-apicomplexan benzoxaborole compound, AN3661. However, unique mutations within the TgCPSF3 catalytic site conferring resistance to AN13762 do not confer cross-protection against AN3661, suggesting a divergent resistance mechanism. Finally, in agreement with the high sequence conservation of CPSF3 between Toxoplasma and Cryptosporidium, AN13762 shows oral efficacy in cryptosporidiosis mouse model, a disease for which new drug development is of high priority.

| S-EPMC7733022 | biostudies-literature

Discovery of kinetochore and spindle assembly checkpoint proteins in apicomplexan parasites

Project description:Kinetochores are multiprotein assemblies that bind chromosomes to the spindle during mitosis. Despite conserved roles, repertoires of kinetochore proteins vary greatly across eukaryotes. In particular, most known components are not clearly detected in a group of parasites known as the Apicomplexa. Furthermore, flexibility in scale of amplification and an apparent incapability to delay cell cycle progression in response to spindle integrity has coined an idea these parasites divide in the absence of spindle checkpoints. In this study, we reunite divergent apicomplexan kinetochore components to a common eukaryotic set and additionally identify 9 kinetochore proteins that share little homology to known proteins. AKiTs are essential for chromosome segregation and show modes of division parallel to eukaryotic metaphase to anaphase transition and spindle assembly checkpoint signaling. These findings suggest conserved spindle assembly checkpoint signaling maintains fidelity during chromosome segregation in apicomplexan parasites.

2023-03-11 | PXD028595 | Pride

Alternative Splicing in Apicomplexan Parasites.

Project description:Alternative splicing is a widespread, essential, and complex component of gene regulation. Apicomplexan parasites have long been recognized to produce alternatively spliced transcripts for some genes and can produce multiple protein products that are essential for parasite growth. Recent approaches are now providing more wide-ranging surveys of the extent of alternative splicing; some indicate that alternative splicing is less widespread than in other model eukaryotes, whereas others suggest levels comparable to those of previously studied groups. In many cases, apicomplexan alternative splicing events appear not to generate multiple alternative proteins but instead produce aberrant or noncoding transcripts. Nonetheless, appropriate regulation of alternative splicing is clearly essential in Plasmodium and Toxoplasma parasites, suggesting a biological role for at least some of the alternative splicing observed. Several studies have now disrupted conserved regulators of alternative splicing and demonstrated lethal effects in apicomplexans. This minireview discusses methods to accurately determine the extent of alternative splicing in Apicomplexa and discuss potential biological roles for this conserved process in a phylum of parasites with compact genomes.

| S-EPMC6381282 | biostudies-literature

Identification of antimalarial compounds that inhibit Apicomplexan AP2 transcription factor proteins in the human malaria parasite Plasmodium falciparum

Project description:Transcription time course of Plasmodium falciparum parasite asexual blood stage progression in the presence of antimalarial drug CID5750730 (Compound C)

2022-05-13 | GSE202876 | GEO

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target Cleavage and Polyadenylation Specificity Factor 3 (CPSF3), the 3’ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of non-transformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional read-through in replication-dependent histones, reduces core histone expression, destabilizes chromatin structure and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.

2024-01-06 | GSE252667 | GEO

Identification of antimalarial compounds that inhibit Apicomplexan AP2 transcription factor proteins in the human malaria parasite Plasmodium falciparum

Project description:Identification of antimalarial compounds that inhibit Apicomplexan AP2 transcription factor proteins in the human malaria parasite Plasmodium falciparum

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Oxaboroles target trypanosome CPSF3

Project description:Oxaboroles target trypanosome CPSF3 - DDD85646 screen

| PRJEB25882 | ENA

The antimalarial natural product salinipostin A identifies essential alpha/beta serine hydrolases involved in lipid metabolism in P. falciparum parasites

Project description:Salinipostin A (Sal A) is a bicyclic phosphotriester natural product isolated from the marine bacterium Salinospora sp. that exhibits potent antimalarial activity. However, the direct targets and mechanisms by which it exerts its effects are poorly understood. Here, we use semi-synthesis to generate a Sal A-derived activity-based probe, enabling the identification of its targets in the human malaria parasite Plasmodium falciparum. All of the identified proteins contain an / serine hydrolase domain and several have been reported as essential for growth of the parasite. One of the essential targets is an uncharacterized protein (PF3D7_1038900, referred to as PfMAGLLP) that displays a high degree of homology to human monoacylglycerol lipase (MAGL). Recombinant expression of this protein confirms that it processes lipid esters as well as a bona fide MAGL acylglyceride substrate. PfMAGLLP is potently inhibited by Sal A, as well as by human MAGL inhibitors and by the anti-obesity drug Orlistat that disrupts lipid metabolism and induces a similar death phenotype in parasites as Sal A. Resistance selection studies with Sal A yielded parasites that showed only a mild reduction in sensitivity. Multiple whole-genome sequenced Sal A-selected clones displayed nonsynonymous mutations in a gene coding for a putative PRELI domain-containing protein (PF3D7_1324400) related to a mitochondrial protein linked to multidrug resistance in Toxoplasma gondii. Together, these data suggest that the antimalarial activity of Sal A results from inhibition of multiple essential serine hydrolases, leading to disruption of lipid metabolism pathways. The combination of the non-essentiality of many of these serine hydrolases in humans and the lack of parasite resistance pathways to fully overcome inhibitor treatment suggest that this class of enzymes represent promising targets for development of next-generation antimalarial agents.

2020-01-24 | PXD016835 | Pride

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