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

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

PROVIDER: PRJNA837583 | ENA |

REPOSITORIES: ENA

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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

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

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

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

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Induction of target genes of AP2-Sp in AP2-O::Sp parasites

Project description:Sporozoite-specific genes were induced in parasites that express AP2-O whose AP2 domain was swapped with that of AP2-Sp. DNA construct encoding AP2 domain of AP2-Sp was introduced into P. bergei schizonts. It was integrated into the locus of the endogenious AP2-O gene, resulting in swap of the AP2-domain (AP2-O::Sp parasites). Gene expression was analyzed in ookinetes cultured for 20h.

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Induction of target genes of AP2-Sp in AP2-O::Sp parasites

Project description:Sporozoite-specific genes were induced in parasites that express AP2-O whose AP2 domain was swapped with that of AP2-Sp.

2009-11-09 | GSE18910 | GEO

Lifecycle progression and sexual development of the apicomplexan parasite Cryptosporidium parvum

Project description:The apicomplexan parasite Cryptosporidium is a leading global cause of severe diarrheal disease and an important contributor to early childhood mortality. Currently there are no fully effective treatments or vaccines available. Transmission of the disease occurs through ingestion of oocysts, through direct contact or contaminated water or food. Oocysts are meiotic spores and the product of parasite sex. Cryptosporidium has a single host lifecycle where both asexual and sexual processes unfold in the intestine of infected hosts. Here we use the new-found ability to genetically engineer Cryptosporidium to make life cycle progression and parasite sex tractable. We derive reporter strains to follow parasite development in culture and infected mice and define the genes that orchestrate sex and oocyst formation through mRNA sequencing of sorted cells. After two days, parasites in cell culture show pronounced sexualization, but productive fertilization does not occur and infection falters. In contrast in infected mice, male gametes successfully fertilize females, leading to meiotic division and sporulation. To rigorously test for fertilization, we devised a two-component genetic crossing assay employing a Cre recombinase activated reporter. Our findings suggest obligate developmental progression towards sex in Cryptosporidium, which has important implications for the treatment and prevention of the infection.

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PFG controls gene expression in female gametocytes cooperatively with AP2-FG [AP2-FG_DIP]

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Project description:Identifying gene expression changes in adipose tissue of lipodystrophic aP2-nSREBP1c trangenic mice Keywords: Genetic modification

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Lifecycle progression and sexual development of the apicomplexan parasite Cryptosporidium parvum

Project description:Lifecycle progression and sexual development of the apicomplexan parasite Cryptosporidium parvum

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