Identification and Characterization of Small Molecule Inhibitors of a Class I Histone Deacetylase from <i>Plasmodium falciparum</i>

Patel, Vipul; Mazitschek, Ralph; Coleman, Bradley I.; Nguyen, Cokey; Urgaonkar, Sameer; Cortese, Joseph F.; Barker, Robert H.; Greenberg, Edward; Tang, Weiping; Bradner, James E.; Schreiber, Stuart L.; Duraisingh, Manoj T.; Wirth, Dyann F.; Clardy, Jon

doi:10.1021/jm801654y

Cited by 76 publications

(96 citation statements)

References 26 publications

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“…Several HDAC inhibitors that are potent inhibitors of asexual blood-stage P. falciparum parasites, including SAHA and TSA, have been shown to inhibit recombinant PfHDAC1 in in vitro enzyme assays (58). We and others have also demonstrated that hyperacetylation of parasite histone and nonhistone proteins and global transcriptional alterations are a functional consequence of HDAC inhibitor exposure in asexual stage parasites (31,32,58,63,69,73,75).…”

Section: Discussionmentioning

confidence: 87%

“…HDACs, enzymes involved in regulating lysine acetylation of histone and nonhistone proteins in eukaryotic cells, are a recognized drug target in asexual stage malaria parasites (30,58,69). Five HDAC-encoding genes have been identified in the P. falciparum genome (70).…”

Section: Discussionmentioning

confidence: 99%

“…While the two class III HDAC homologues, PfSir2a (PlasmoDB gene accession number PF3D7_1328800) and PfSir2b (PlasmoDB gene accession number PF3D7_1451400), are not essential to asexual stage P. falciparum survival in vitro (71,72), the three class I and II HDAC homologues, PfHDAC1 to PfHDAC3 (PlasmoDB gene accession numbers PF3D7_0925700, PF3D7_1472200, and PF3D7_1008000, respectively), are potential targets of antimalarial HDAC inhibitors. PfHDAC1 has Ͼ50% homology to other mammalian HDACs (43), and a recombinant form of this protein can be potently inhibited by antimalarial HDAC inhibitors like TSA and SAHA (58). In contrast, PfHDAC2 and PfHDAC3 share very little sequence homology with any mammalian HDACs and have not been characterized.…”

Section: Discussionmentioning

confidence: 99%

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Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Trenholme

Marek

Duffy

et al. 2014

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Trenholme

Marek

Duffy

et al. 2014

Antimicrob Agents Chemother

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“…Blood-stage Plasmodium can be killed with many drugs which inhibit histone-modifying enzymes. These include the histone acetylase inhibitors curcumin and anacardic acid (23,24), the sirtuin inhibitor nicotinamide (88), and a multitude of known and novel inhibitors of type 1 and type 2 histone deacetylases (1,2,4,28,70,83). These results suggest that histone modification is crucial for normal parasite development, and deacetylase inhibitors are therefore under investigation as antimalarial drugs (3).…”

Section: What Experimental Tools Have Been Used To Study Plasmodium Ementioning

confidence: 99%

Epigenetics in Plasmodium: What Do We Really Know?

Merrick

Duraisingh

2010

Eukaryot Cell

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In the burgeoning field of Plasmodium gene expression, there are-to borrow some famous words from a former U.S. Secretary of Defense-"known knowns, known unknowns, and unknown unknowns." This is in itself an important achievement, since it is only in the past decade that facts have begun to move from the third category into the first. Nevertheless, much remains in the middle ground of known or suspected "unknowns." It is clear that the malaria parasite controls vital virulence processes such as host cell invasion and cytoadherence at least partly via epigenetic mechanisms, so a proper understanding of epigenetic transcriptional control in this organism should have great clinical relevance. Plasmodium, however, is an obligate intracellular parasite: it operates not in a vacuum but rather in the complicated context of its metazoan hosts. Therefore, as valuable data about the parasite's basic epigenetic machinery begin to emerge, it becomes increasingly important to relate in vitro studies to the situation in vivo. This review will focus upon the challenge of understanding Plasmodium epigenetics in an integrated manner, in the human and insect hosts as well as the petri dish. WHY DOES EPIGENETICS MATTER IN PLASMODIUM?The malaria parasite has a complicated life cycle involving several functionally distinct forms living in two very different host species. It must be able to perform rapid transitions between morphological states and also long-term antigenic variation to sustain chronic infections in human hosts. To achieve all this, the parasite employs various types of regulation, including transcriptional and posttranscriptional regulation of gene expression, translational repression, and posttranslational protein modification. While several of these regulatory modes are suited to respond rapidly to host conditions during an acute infection or a life cycle transition, only the epigenetic control of gene expression can then maintain that "imprinted" pattern in later generations. (The term "epigenetic" will be used here to refer to the heritable marking of genetic material without alterations in the actual genetic code.) Epigenetic mechanisms of transcriptional control are thus likely to act in at least three major areas of Plasmodium biology.The first area is the cascade of changing gene expression which occurs during asexual replication in the human bloodstream. This is the most studied stage of the life cycle and the one which causes all the clinical symptoms of malaria. Plasmodium falciparum, the main Plasmodium species responsible for human mortality, has an unusual, formulaic mode of gene expression during its 48-h developmental process inside the erythrocyte, implying tight and integrated genome-wide regulation of transcription (13,62,65). It was initially thought that the Plasmodium genus had a striking paucity of classical transcription factors because few could be found in the sequenced genome of P. falciparum (49), and epigenetics was postulated as an alternative primary mode of transcriptional regulation. ...

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“…It would be of great interest, in order to gain further insight into the precise function of Pfcrk-3, to identify which of the several putative HDACs (one class I HDAC, two class II HDACs, and two class III sirtuins [44]) encoded by the P. falciparum genome is responsible for the activity we observed to be associated with HA-Pfcrk-3. Sensitivity to nicotinamide suggests that a class III HDAC, such as Pfsir2, is involved (45), but caution must be exercised until the enzyme is experimentally identified.…”

Section: Discussionmentioning

confidence: 99%

A Plasmodium falciparum Transcriptional Cyclin-Dependent Kinase-Related Kinase with a Crucial Role in Parasite Proliferation Associates with Histone Deacetylase Activity

et al. 2010

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Cyclin-dependent protein kinases (CDKs) are key regulators of the eukaryotic cell cycle and of the eukaryotic transcription machinery. Here we report the characterization of Pfcrk-3 (Plasmodium falciparum CDK-related kinase 3; PlasmoDB identifier PFD0740w), an unusually large CDK-related protein whose kinase domain displays maximal homology to those CDKs which, in other eukaryotes, are involved in the control of transcription. The closest enzyme in Saccharomyces cerevisiae is BUR1 (bypass upstream activating sequence requirement 1), known to control gene expression through interaction with chromatin modification enzymes. Consistent with this, immunofluorescence data show that Pfcrk-3 colocalizes with histones. We show that recombinant Pfcrk-3 associates with histone H1 kinase activity in parasite extracts and that this association is detectable even if the catalytic domain of Pfcrk-3 is rendered inactive by site-directed mutagenesis, indicating that Pfcrk-3 is part of a complex that includes other protein kinases. Immunoprecipitates obtained from extracts of transgenic parasites expressing hemagglutinin (HA)-tagged Pfcrk-3 by using an anti-HA antibody displayed both protein kinase and histone deacetylase activities. Reverse genetics data show that the pfcrk-3 locus can be targeted only if the genetic modification does not cause a loss of function. Taken together, our data strongly suggest that Pfcrk-3 fulfils a crucial role in the intraerythrocytic development of P. falciparum, presumably through chromatin modification-dependent regulation of gene expression.Plasmodium falciparum, the protozoan parasite responsible for the most virulent form of human malaria, causes 1 to 3 millions deaths annually, mostly among children in sub-Saharan Africa. This mortality is expected to rise with the global emergence and spread of drug-resistant parasites, making the discovery of alternative control agents an urgent task (43). The identification of potential targets is now greatly facilitated by the availability of genomic databases for several species of the Plasmodium genus (www.plasmoDB.org) (49). Plasmodium cell cycle regulators represent attractive candidate targets for intervention, because (i) their activities are most probably essential to parasite survival, and (ii) the overall organization of the cell cycle in malaria parasites differs considerably from that in mammalian cells; this is reflected by atypical properties of the enzymatic machinery controlling cell cycle progression, suggesting that specific inhibition is achievable (12,15).The progression of the eukaryotic cell cycle is tightly controlled by a family of protein kinases, the cyclin-dependent kinases (CDKs), whose active forms are composed of a catalytic subunit (CDK) and a regulatory subunit (cyclin) (39). While several mammalian CDKs (CDK1, -2, -3, -4, -6, and -7) function in cell cycle control, others (CDK8, -9, -10, and -11) are part of the transcription machinery. CDK7 is a regulator both of cell cycle progression (through its activity as a CDKactiva...

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Identification and Characterization of Small Molecule Inhibitors of a Class I Histone Deacetylase from Plasmodium falciparum

Cited by 76 publications

References 26 publications

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Epigenetics in Plasmodium: What Do We Really Know?

A Plasmodium falciparum Transcriptional Cyclin-Dependent Kinase-Related Kinase with a Crucial Role in Parasite Proliferation Associates with Histone Deacetylase Activity

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