Malaria: Targeting parasite and host cell kinomes

Doerig, Christian; Abdi, Abdirahman; Bland, Nicholas D.; Eschenlauer, Sylvain C.P.; Dorin‐Semblat, Dominique; Fennell, Clare; Halbert, Jean; Holland, Zoë; Nivez, Marie-Paule; Semblat, Jean-Philippe; Sicard, Audrey; Reininger, Luc

doi:10.1016/j.bbapap.2009.10.009

Cited by 79 publications

(66 citation statements)

References 69 publications

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“…In the protozoan field, PKs have gained interest due to their verified function e.g in cell cycle regulation. Plasmodium CDKs (cell cycle-dependent kinases) were shown to be potential targets of CDK inhibitors designed for mammals, which opens the perspective for alternative treatment concepts [169][170][171]. In addition, PKs are likely involved in cell cycle control, differentiation, and stress response during the complex life-cycles of other protozoan parasites such as Trypanosoma and Leishmania [172][173][174].…”

Section: Resultsmentioning

confidence: 99%

Protein Kinases as Potential Targets for Novel Anti-Schistosomal Strategies

Beckmann

Leutner²,

Gouignard³

et al. 2012

cpd

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Schistosome parasites are the causative pathogens of schistosomiasis (bilharzia), a disease of worldwide significance. In terms of patient numbers, schistosomiasis ranks second to malaria as a parasitosis affecting more than 200 million people of the tropics and subtropics. Since the 1970s Praziquantel (PZQ) is the drug of choice and nearly exclusively used for treatment. However, drug resistance is an increasing threat, particularly with respect to large-scale PZQ administration programs. Last decade´s research indicated that resistance against PZQ can be induced under laboratory conditions, and field studies provided first indications for the possibility of reduced PZQ efficacy. Furthermore, clear evidence for the molecular armamentarium of schistosomes with multidrug transporters was found, one of which was responding to PZQ challenge. Also the development of a vaccine still represents an elusive goal, although effort and time have been invested in this subject. In light of these facts it is commonly accepted that new drugs are urgently needed. Research on signal transduction processes in Schistosoma mansoni has provided an unexpected and novel perspective towards this end. Molecular, biochemical, and physiological studies elucidating principles of schistosome development have demonstrated the essential role of protein kinases (PKs). In humans, PKs are known to be involved in cancer development. Since a variety of approved anticancer drugs targeting PKs exist, first studies have been performed to investigate whether these drugs are able to also inhibit schistosome PKs. Indeed, promising results have been obtained indicating the potential of PKs as privileged targets for new concepts in fighting schistosomes.

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Section: Resultsmentioning

confidence: 99%

Protein Kinases as Potential Targets for Novel Anti-Schistosomal Strategies

Beckmann

Leutner²,

Gouignard³

et al. 2012

cpd

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“…The determination of the essential protein kinases in the blood stage of P. falciparum [19] not only reveals the protein kinases that might constitute targets for novel antimalarial therapy but also provides a framework to identify key phospho-signalling pathways [55]. Identifying kinase substrates would represent a significant advance in our understanding of such pathways.…”

Section: Plasmodium Phosphoproteomicsmentioning

confidence: 99%

An evolutionary perspective on the kinome of malaria parasites

Talevich

Tobin

Kannan

et al. 2012

Phil. Trans. R. Soc. B

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Malaria parasites belong to an ancient lineage that diverged very early from the main branch of eukaryotes. The approximately 90-member plasmodial kinome includes a majority of eukaryotic protein kinases that clearly cluster within the AGC, CMGC, TKL, CaMK and CK1 groups found in yeast, plants and mammals, testifying to the ancient ancestry of these families. However, several hundred millions years of independent evolution, and the specific pressures brought about by first a photosynthetic and then a parasitic lifestyle, led to the emergence of unique features in the plasmodial kinome. These include taxon-restricted kinase families, and unique peculiarities of individual enzymes even when they have homologues in other eukaryotes. Here, we merge essential aspects of all three malaria-related communications that were presented at the Evolution of Protein Phosphorylation meeting, and propose an integrated discussion of the specific features of the parasite's kinome and phosphoproteome.

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“…Surprisingly, despite the fact that protein phosphorylation is a universal regulatory mechanism demonstrated as a druggable target in many human diseases, the potential of targeting the largely divergent protein kinases and phospho-signalling cascades of malaria parasites has been unexploited 2,3 . One of the factors contributing to this neglect is the serious paucity of information regarding the role played by phosphorylation in the biology of the most virulent human malaria parasite, Plasmodium falciparum.…”

mentioning

confidence: 99%

“…The significant phylogenetic diversity between the human and malarial kinomes could possibly provide the basis for selective targeting of the malarial kinome 2 . Although this is an attractive notion, there is very little information regarding the role of protein phosphorylation in Plasmodium biology, and hence predicting the potential efficacy and cellular effects of drugs targeting malarial kinases and phosphorylation pathways is difficult.…”

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confidence: 99%

Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum

et al. 2011

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The role of protein phosphorylation in the life cycle of malaria parasites is slowly emerging. Here we combine global phospho-proteomic analysis with kinome-wide reverse genetics to assess the importance of protein phosphorylation in Plasmodium falciparum asexual proliferation. We identify 1177 phosphorylation sites on 650 parasite proteins that are involved in a wide range of general cellular activities such as DnA synthesis, transcription and metabolism as well as key parasite processes such as invasion and cyto-adherence. several parasite protein kinases are themselves phosphorylated on putative regulatory residues, including tyrosines in the activation loop of PfGsK3 and PfCLK3; we show that phosphorylation of PfCLK3 Y526 is essential for full kinase activity. A kinome-wide reverse genetics strategy identified 36 parasite kinases as likely essential for erythrocytic schizogony. These studies not only reveal processes that are regulated by protein phosphorylation, but also define potential anti-malarial drug targets within the parasite kinome.

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Malaria: Targeting parasite and host cell kinomes

Cited by 79 publications

References 69 publications

Protein Kinases as Potential Targets for Novel Anti-Schistosomal Strategies

Protein Kinases as Potential Targets for Novel Anti-Schistosomal Strategies

An evolutionary perspective on the kinome of malaria parasites

Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum

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