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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylases (HDACs) regulate many important physiological processes and the discovery of small molecules that modulate HDAC activity has both academic and clinical relevance. HDAC inhibitors, most notably SAHA, have been pursued as cancer chemotherapeutics but may be useful in treating psychiatric disorders, malaria, and other diseases. Herein, we describe an inexpensive and robust assay, based on fluorescence polarization, for HDAC ligand discovery. The assay is well suited for high-throughput screening and enzyme kinetic studies.
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PMID:Development of a fluorescence polarization based assay for histone deacetylase ligand discovery. 1843 May 69

Histone deacetylases (HDAC) are potential targets for the development of new antimalarial drugs. The growth of Plasmodium falciparum and other apicomplexans can be suppressed in the presence of potent HDAC inhibitors in vitro and in vivo; however, in vivo parasite suppression is generally incomplete or reversible after the discontinuation of drug treatment. Furthermore, most established HDAC inhibitors concurrently show broad toxicities against parasites and human cells and high drug concentrations are required for effective antimalarial activity. Here, we report on HDAC inhibitors that are potent against P. falciparum at subnanomolar concentrations and that have high selectivities; the lead compounds have mean 50% inhibitory concentrations for the killing of the malaria parasite up to 950 times lower than those for the killing of mammalian cells. These potential drugs improved survival and completely and irreversibly suppressed parasitemia in P. berghei-infected mice.
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PMID:Novel inhibitor of Plasmodium histone deacetylase that cures P. berghei-infected mice. 1922 22

Tudor Staphylococcal Nuclease (p100 or SND1), a member of the micronuclease family is a multifunctional protein that plays a key role(s) in transcription and splicing processes in many eukaryotic cells. PfTudor-SN, a Plasmodium homolog of the human p100 protein is a structurally conserved protein; however molecular details of its function are not yet understood. Our previous studies have shown that PfTudor-SN binds RNA and it is possible to selectively inhibit parasite growth by PfTudor-SN specific drugs. In the present study, we identified the molecular interactions between Plasmodium falciparum Tudor-SN and twelve Plasmodium proteins such as Histone h2A, SPT2 (a transcriptional regulator), a Cold-shock DNA binding protein in a bacterial two-hybrid screen. To get further insight into some of these interactions, we mapped the interaction domain in PfTudor-SN protein using the yeast two-hybrid system. Of these proteins, Plasmodium N-methyl-d-aspartate receptor associated protein, PfUbiquitin conjugating enzyme and Cold-shock DNA binding protein showed interaction with the SN domains of PfTudor-SN. Immuno-localization studies of the interacting proteins showed their presence predominantly in the nucleus, which inevitably suggests the molecular interactions between these proteins and PfTudor-SN. Furthermore, we also identified a molecular interaction between the Tudor domain of PfTudor-SN protein and Plasmodium spliceosomal Sm protein, PfSmD1 advocating the role of PfTudor-SN in the spliceosome assembly. Together, these results suggest multiple role(s) for PfTudor-SN protein mainly in nuclear and splicing processes at asexual blood stages of the malaria parasite.
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PMID:Plasmodium falciparum Tudor Staphylococcal Nuclease interacting proteins suggest its role in nuclear as well as splicing processes. 2071 34

Histone deacetylases (HDACs) are important enzymes that effect post-translational modifications of proteins by altering the acetylation state of lysine residues. HDACs control epigenetic changes that trigger cell transformation and proliferation of transformed cells associated with many diseases. These enzymes are validated drug targets for some types of cancer and are promising therapeutic targets for a range of other diseases, including malaria. Annually, there are ~500 million clinical cases of malaria and ~0.8-1.2 million deaths. There is no licensed vaccine for preventing malaria, and parasites that cause malaria are becoming resistant to current drugs, necessitating the search for new therapies. HDAC inhibitors are emerging as a promising new class of antimalarial drugs with potent and selective action against Plasmodium parasites in vitro. Recent studies on the effects of HDAC inhibitors on the growth and development of P. falciparum have provided important new information on transcriptional regulation in malaria parasites and have validated the potential of this class of inhibitors for malaria therapy. To realise effective HDAC inhibitors for clinical trials, next generation inhibitors must not inhibit other human HDACs or proteins required for normal human physiology, be highly selective in killing parasites in vivo without killing normal host cells, and have improved bioavailability and pharmacokinetic profiles. This review summarizes current knowledge about malaria parasite HDACs and HDAC inhibitors with antimalarial properties, and provides insights for their development into new drugs for treatment of malaria.
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PMID:Towards histone deacetylase inhibitors as new antimalarial drugs. 2260 40

Plasmodium falciparum, one of the deadliest parasites on earth causes human malaria resulting one million deaths annually. Central to the parasite pathogenicity and morbidity is the switching of parasite virulence (var) gene expression causing host immune evasion. The regulation of Plasmodium var gene expression is poorly understood. The complex life cycle of Plasmodium and mutually exclusive expression pattern of var genes make this disease difficult to control. Recent studies have demonstrated the pivotal role of epigenetic mechanism for control of coordinated expression of var genes, important for various clinical manifestations of malaria. In this review, we discuss about different Plasmodium histones and their various modifications important for gene expression and gene repression.Contribution of epigenetic mechanism to understand the var gene expression is also highlighted. We also describe in details P. falciparum nuclear architecture including heterochromatin, euchromatin and telomeric regions and their importance in subtelomeric and centrally located var gene expression. Finally, we explore the possibility of using Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC)inhibitors against multi-drug resistance malaria parasites to provide another line of treatment for malaria.
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PMID:Plasmodium falciparum: epigenetic control of var gene regulation and disease. 2315 Feb 71

Histone modifications are important regulators of gene expression in all eukaryotes. In Plasmodium falciparum, these epigenetic marks regulate expression of genes involved in several aspects of host-parasite interactions, including antigenic variation. While the identities and genomic positions of many histone modifications have now been cataloged, how they are targeted to defined genomic regions remains poorly understood. For example, how variant antigen encoding loci (var) are targeted for deposition of unique histone marks is a mystery that continues to perplex the field. Here we describe the recruitment of an ortholog of the histone modifier SET2 to var genes through direct interactions with the C-terminal domain (CTD) of RNA polymerase II. In higher eukaryotes, SET2 is a histone methyltransferase recruited by RNA pol II during mRNA transcription; however, the ortholog in P. falciparum (PfSET2) has an atypical architecture and its role in regulating transcription is unknown. Here we show that PfSET2 binds to the unphosphorylated form of the CTD, a property inconsistent with its recruitment during mRNA synthesis. Further, we show that H3K36me3, the epigenetic mark deposited by PfSET2, is enriched at both active and silent var gene loci, providing additional evidence that its recruitment is not associated with mRNA production. Over-expression of a dominant negative form of PfSET2 designed to disrupt binding to RNA pol II induced rapid var gene expression switching, confirming both the importance of PfSET2 in var gene regulation and a role for RNA pol II in its recruitment. RNA pol II is known to transcribe non-coding RNAs from both active and silent var genes, providing a possible mechanism by which it could recruit PfSET2 to var loci. This work unifies previous reports of histone modifications, the production of ncRNAs, and the promoter activity of var introns into a mechanism that contributes to antigenic variation by malaria parasites.
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PMID:Recruitment of PfSET2 by RNA polymerase II to variant antigen encoding loci contributes to antigenic variation in P. falciparum. 2439 4

Histone lysine methyltransferase (HKMT) are histone-modifying enzymes that catalyze the transfer of methyl groups to lysine and arginine residues of histone protein. HKMTs have been involved in transcriptional regulation of various proteins in organisms. Malaria parasite also has HKMT, which plays a major role in parasite development and pathogenesis and also in regulation of various biological process and pathways. Our aim is to study fundamental biology of key molecules involved in the survival of Plasmodium falciparum and use these to develop efficient synthetic peptides and chemical compounds. As a first step in this direction, we computationally predicted the three-dimensional structure of HKMT of P. falciparum (PfHKMT) by using iterative threading assembly refinement. The PfHKMT three-dimensional model was validated using PROCHECK and docked with known HKMT inhibitor Bix01294 using Autodock. Our initial results are encouraging and indicate that structural analysis of PfHKMT could be important in developing novel synthetic molecules against malaria.
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PMID:Designing synthetic drugs against Plasmodium falciparum: a computational study of histone-lysine N-methyltransferase (PfHKMT). 2479 60

Histone modification profiles are predictive of gene expression and most of the knowledge gained is acquired through studies done in higher eukaryotes. However, genome-wide studies involving Plasmodium falciparum, the causative agent of malaria, have been rather few, at lower resolution (mostly using ChIP-on-chip), and covering limited number of histone modifications. In our recent study [1], we have performed extensive genome-wide analyses of multiple histone modifications including the active (H3K4me2, H3K4me3, H3K9ac, H3K14ac, H3K27ac and H4ac), inactive (H3K9me3 and H3K27me3), elongation (H3K79me3) and regulatory element (H3K4me1) in a stage-specific manner. Furthermore, we used a ligation-based method suitable for sequencing homopolymeric stretches as seen in P. falciparum for next-generation sequencing library amplification [2], enabling highly quantitative analysis of the extremely AT-rich P. falciparum genome. Our recently published study suggests that transcription regulation by virtue of poised chromatin and differential histone modifications is unique to P. falciparum [1]. Here we describe the experiments, quality controls and chromatin immunoprecipitation-sequencing data analysis of our associated study published in Epigenetics and Chromatin [1]. Stage-specific ChIP-sequencing data for histone modifications is submitted to Gene Expression Omnibus (GEO) database under the accession number GSE63369.
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PMID:Plasmodium falciparum epigenome: A distinct dynamic epigenetic regulation of gene expression. 2698 68

Fungi are generally benign members of the human mucosal flora or live as saprophytes in the environment. However, they can become pathogenic, leading to invasive and life threatening infections in vulnerable patients. These invasive fungal infections are regarded as a major public health problem on a similar scale to tuberculosis or malaria. Current treatment for these infections is based on only four available drug classes. This limited therapeutic arsenal and the emergence of drug-resistant strains are a matter of concern due to the growing number of patients to be treated, and new therapeutic strategies are urgently needed. Adaptation of fungi to drug pressure involves transcriptional regulation, in which chromatin dynamics and histone modifications play a major role. Histone deacetylases (HDACs) remove acetyl groups from histones and actively participate in controlling stress responses. HDAC inhibition has been shown to limit fungal development, virulence, biofilm formation, and dissemination in the infected host, while also improving the efficacy of existing antifungal drugs toward Candida spp. In this article, we review the functional roles of HDACs and the biological effects of HDAC inhibitors on Candida spp., highlighting the correlations between their pathogenic effects in vitro and in vivo. We focus on how HDAC inhibitors could be used to treat invasive candidiasis while also reviewing recent developments in their clinical evaluation.
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PMID:Histone Deacetylases and Their Inhibition in Candida Species. 2754 5

Malaria parasites can readily sense and adapt to environmental changes, thus making the control and eradication of this disease difficult. Molecular studies have unraveled a very tightly coordinated transcriptional machinery governed by complex regulatory mechanisms including chromatin modification and spatiotemporal compartmentalization. Histone modifying enzymes play key roles in the regulation of chromatin modification and gene expression, which are associated with cell cycle progression, antigenic variation and immune evasion. Here, we present a comprehensive review of the key regulators of the Plasmodium falciparum histone acetylome; histone acetyltransferases (HATs); and histone deacetylases (HDACs). We describe the genome-wide occurrence of HATs and HDACs in the P. falciparum genome and identify novel, as well as previously unclassified HATs. We re-confirm the presence of five known HDACs and identify, a novel putative HDAC. Interestingly, we identify several HATs and HDACs with unique and noncanonical domain combinations indicating their involvement in other associated functions. Moreover, the phylogenetic analyses of HATs and HDACs suggest that many of them are close to the prokaryotic systems and thus potential candidates for drug development. Our review deciphers the phylogeny of HATs and HDACs of the malaria parasite, investigates their role in drug-resistance generation, and highlights their potential as therapeutic targets.
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PMID:Genome-wide survey and phylogenetic analysis of histone acetyltransferases and histone deacetylases of Plasmodium falciparum. 2928 96


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