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

ABSTRACT: 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.

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE208155 | GEO | 2022/07/15

REPOSITORIES: GEO

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A knockout screen of ApiAP2 genes reveals networks of interacting transcriptional regulators controlling the Plasmodium life cycle.

Project description:The family of apicomplexa-specific proteins with DNA binding AP2 domains (ApiAP2s) includes sequence-specific transcription factors that are key regulators of development in malaria parasites. However, functions for the majority of ApiAP2 genes remain unknown. Here, a systematic knockout screen in Plasmodium berghei identifies ten ApiAP2 genes essential for mosquito transmission, of which four are critical for the formation of infectious ookinetes and three for sporogony. We describe unexpected non-essential functions for AP2-O and AP2-SP proteins in blood stages and identify AP2-G2 as a universal repressor active in both, asexual and sexual stages. Comparative transcriptomics across mutants and developmental stages reveals clusters of co-regulated genes with shared cis elements in their promoters, whose expression can be controlled positively or negatively by different ApiAP2 gene deletions. We propose that stage-specific interactions between ApiAP2 proteins on partly overlapping sets of target genes generate the complex transcriptional network that controls the Plasmodium life cycle.

2017-02-08 | PXD005180 | Pride

Transcriptome changes during inducible gametocytogenesis in Plasmodium berghei parasites

Project description:During the malaria infection, Plasmodium parasites invade the host’s red blood cells where they can differentiate into two different life forms. The majority will replicate asexually and infect new erythrocytes. A small percentage, however, will transform into gametocytes – a specialized sexual stage able to survive and develop when taken up by Anopheles mosquito. As the gametocytes ensure the parasite’s transmission to a new host, their generation is an attractive target for new antimalarial interventions. The molecular mechanisms controlling gametocytogenesis, however, remain largely unknown due to the technical challenges: the early gametocytes are morphologically indistinguishable from asexual parasites and present in very low numbers during the infection. Recently, AP2-G - a transcription factor from an apicomplexa-specific apiAP2 family – was described as indispensable for gametocyte commitment in both human malaria parasite Plasmodium falciparum and rodent malaria model Plasmodium berghei. Therefore, we have decided to test whether the overexpression of this factor alone could increase gametocyte production and enable the investigation of uncharacterised, earliest stages of gametocyte development. To this end, we have engineered PBGAMi - a Plasmodium berghei line, in which all parasites were ap2-g deficient by default but able to overexpress it when induced with rapamycin. While the control parasites (PBGAMi R-), as expected, differentiated into asexual forms (schizonts) only, almost all rapamycin-treated parasites (PBGAMi R+) transformed into gametocytes. We used the generated line to perform RNA-seq analysis of the R- and R+ populations at different time points of their development and identify the changes arising between them, mapping the sequence of events leading to the formation of gametocytes.

2018-06-30 | GSE110201 | GEO

Transcriptome changes during inducable gametocytogenesis in Plasmodium berghei parasites

2021-03-13 | GSE168817 | GEO

Global Transcriptional Repression: Initial and Essential Step for Plasmodium Sexual Development [ChIP-seq]

Project description:Gametocytes are nonreplicative sexual forms that mediate malaria transmission to a mosquito vector. They are generated from asexual blood stage parasites, which proliferate in the circulation. However, it remains largely unknown as to how this transition is genetically regulated. Here, we report that an Apetala2 (AP2) family transcription factor, AP2-G2, regulates the transition as a transcriptional repressor. Disruption of AP2-G2 in the rodent malaria parasites, Plasmodium berghei, did not prevent commitment to the sexual stage but halted their development before manifesting sex-specific morphologies. ChIP-seq analysis revealed that AP2-G2 targets approximately 1,500 genes and recognizes a five-base motif on their promoters. Most of these target genes are required for asexual proliferation in the blood by the parasites, thereby suggesting that AP2-G2 blocks the program for asexual replication of parasites in the blood. DNA microarray analysis showed that the identified targets constituted approximately 70% of the upregulated genes in AP2-G2-depleted parasites, and a promoter assay using a centromere plasmid demonstrated that the binding motif functions as a cis-acting negative regulatory element. These results suggest that global transcriptional repression, which occurs during the initial phase of gametocytogenesis, is an essential step to promote conversion to the sexual stage.

2015-10-01 | GSE66189 | GEO

Global Transcriptional Repression: Initial and Essential Step for Plasmodium Sexual Development [expression array]

2015-10-01 | GSE66188 | 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

| PRJNA837583 | ENA

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

GDV1 triggers sexual conversion and differentiation in malaria parasites by antagonizing HP1-dependent gene silencing

Project description:Malaria is caused by Plasmodium parasites that proliferate through iterative cycles of intra-erythrocytic replication. During each cycle a small number of parasites differentiate into gametocytes, the only forms able to infect the mosquito vector and transmit malaria. Sexual commitment is triggered by activation of AP2-G, the master transcriptional regulator of gametocytogenesis. Heterochromatin protein 1 (HP1)-dependent silencing of ap2-g prevents sexual conversion and secures proliferation. Here, we identify gametocyte development 1 (GDV1) as the first upstream activator of the sexual differentiation pathway in P. falciparum. Induction of GDV1 expression is sufficient to activate AP2-G expression and sexual differentiation. We found that GDV1 targets heterochromatin and triggers HP1 eviction preferentially at ap2-g and other gametocyte-specific genes. We further demonstrate that GDV1-dependent activation of ap2-g is controlled via a gdv1 antisense RNA. In summary, we identify GDV1 as an unprecedented cell fate decision factor that induces sexual differentiation by antagonizing HP1-dependent gene silencing.

2018-05-04 | GSE94901 | GEO

A conserved metabolic signature associated with response to fast-acting antimalarial agents

Project description:<p>Characterizing the mode of action of antimalarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of antimalarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry (LC-MS) and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone (ATQ). A slow acting antimalarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5 h window of drug exposure. In contrast, fast killing drugs, DHA and the spiroindolone (NITD246) elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of haemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described novel class of antimalarial agents of the 5-aryl-2-amino-imidazothiadiazole (ITD) class also exhibited a fast-acting profile that also featured peptide losses indicative of disrupted haemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast acting antimalarial compounds generate similar biochemical signatures in <em>Plasmodium</em> pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates.</p>

2023-09-27 | MTBLS6580 | MetaboLights

Transcription activated by AP2-Z in early zygote plays an essential role in Plasmodium ookinete development [RNA-seq]

Project description:Plasmodium berghei transcriptomes of wild-type and ap2-z knockout parasites [ap2-z(-)] were analyzed at 6 hours post starting ookinete culture (hpoc).

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