Protein Kinases as Drug Targets in the Treatment of Alveolar Echinococcosis

Brehm, Klaus

doi:10.1002/9783527675401.ch17

Cited by 2 publications

(4 citation statements)

References 54 publications

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“…Proteases, G-protein-coupled receptors (GPCR) and ion channels are other groups of "drugable" targets, many of which are expressed in the E. multilocularis metacestode (Tsai et al, 2013). Of prominent interest for drug development against echinococcosis should also be the set of 250-300 kinases identified in the Echinococcus genome (Brehm, 2014;Tsai et al, 2013). Due to the fact that kinases bind both their substrate and ATP, they are prone to enzymatic inhibition by small molecule compounds and many of the currently available kinase inhibitors actually interfere with the ATP binding pocket (Brehm, 2014).…”

Section: Echinococcus Genomicsmentioning

confidence: 99%

“…Of prominent interest for drug development against echinococcosis should also be the set of 250-300 kinases identified in the Echinococcus genome (Brehm, 2014;Tsai et al, 2013). Due to the fact that kinases bind both their substrate and ATP, they are prone to enzymatic inhibition by small molecule compounds and many of the currently available kinase inhibitors actually interfere with the ATP binding pocket (Brehm, 2014). Furthermore, due to their importance in malignant transformation, the biochemistry of kinases is exceptionally well studied and research has already brought up a plethora of inhibitory compounds, many of which are currently in use to treat various forms of cancer (Brehm, 2014).…”

Section: Echinococcus Genomicsmentioning

confidence: 99%

“…Furthermore, due to their importance in malignant transformation, the biochemistry of kinases is exceptionally well studied and research has already brought up a plethora of inhibitory compounds, many of which are currently in use to treat various forms of cancer (Brehm, 2014). Several prominent kinase inhibitors such as Imatinib, directed against Abl-kinases, BI 2536 (Polo-like kinase) or pyridinylimidazoles (p38 MAPK) have already been shown to exert anti-Echinococcus activities in vitro by inhibition of the orthologous parasite factors (Gelmedin et al, 2008;Hemer et al, 2014;Schubert et al, 2014) and are thus promising lead compounds for the design of related small molecule compounds that show a high specificity for parasite kinases (Brehm, 2014). Interestingly, genomic and transcriptomic analyses also revealed why some drugs are not effective against larval cestodes.…”

Section: Echinococcus Genomicsmentioning

confidence: 99%

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Recent advances in Echinococcus genomics and stem cell research

Koziol

Brehm

2015

Veterinary Parasitology

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Alveolar and cystic echinococcosis, caused by the metacestode larval stages of the tapeworms Echinococcus multilocularis and Echinococcus granulosus, respectively, are life-threatening diseases and very difficult to treat. The introduction of benzimidazole-based chemotherapy, which targets parasite β-tubulin, has significantly improved the life-span and prognosis of echinococcosis patients. However, benzimidazoles show only parasitostatic activity, are associated with serious adverse side effects and have to be administered for very long time periods, underlining the need for new drugs. Very recently, the nuclear genomes of E. multilocularis and E. granulosus have been characterised, revealing a plethora of data for gaining a deeper understanding of host-parasite interaction, parasite development and parasite evolution. Combined with extensive transcriptome analyses of Echinococcus life cycle stages these investigations also yielded novel clues for targeted drug design. Recent years also witnessed significant advancements in the molecular and cellular characterisation of the Echinococcus 'germinative cell' population, which forms a unique stem cell system that differs from stem cells of other organisms in the expression of several genes associated with the maintenance of pluripotency. As the only parasite cell type capable of undergoing mitosis, the germinative cells are central to all developmental transitions of Echinococcus within the host and to parasite expansion via asexual proliferation. In the present article, we will briefly introduce and discuss recent advances in Echinococcus genomics and stem cell research in the context of drug design and development. Interestingly, it turns out that benzimidazoles seem to have very limited effects on Echinococcus germinative cells, which could explain the high recurrence rates observed after chemotherapeutic treatment of echinococcosis patients. This clearly indicates that future efforts into the development of parasitocidal drugs should also target the parasite's stem cell system.

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Section: Echinococcus Genomicsmentioning

confidence: 99%

Section: Echinococcus Genomicsmentioning

confidence: 99%

Section: Echinococcus Genomicsmentioning

confidence: 99%

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Recent advances in Echinococcus genomics and stem cell research

Koziol

Brehm

2015

Veterinary Parasitology

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“…Protein kinases (PKs): Protein kinase inhibitors, e.g. pyridinylimidazoles (targeting MAPK) [61] , and Imatinib (targeting Polo-like kinase) [62] exhibited inhibitory activities in vitro. It is worth mentioning that MAPK pathway is a conserved signal transduction pathway utilized to transmit extracellular signals, e.g.…”

Section: Cytochrome C Complex (Cyt C)mentioning

confidence: 99%

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part III: Helminths

Abaza

2022

Parasitologists United Journal

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The term "magic bullet" was chosen to explain how a drug kills the pathogen with a greater affinity and specificity to its target without effecting its orthologue in human. The ideal parasite target is a molecule essential for its viability, growth, proliferation, and differentiation. The majority of commonly administered anthelminthics target either neuromuscular elements, or metabolic pathways. On the other hand, genomics studies combined with transcriptome analyses revealed advanced information in understanding hostparasite interactions that yielded clues for new strategies in identification of new parasite targets and designing novel inhibitors. In fact, next generation sequencing technology provides unique opportunities to understand parasites molecular biology and their role in parasite-host interactions. Besides, drug repurposing is a promising approach to expand the pool of molecules with potent inhibitory activity against a specific parasite target. The present review aims to highlight the proposed potential helminth drug targets with special emphasis on the major tropical diseases such as schistosomiasis, hydatid cyst, lymphatic filariasis, onchocerciases and soil transmitted diseases. The review also highlights hypothesized potential targets for future development of novel anthelminthics utilizing aminoacyl-tRNA synthetase and the 20S core proteasome, as well as new strategies targeting parasitic response to overcome host mechanistic target of rapamycin.

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Protein Kinases as Drug Targets in the Treatment of Alveolar Echinococcosis

Cited by 2 publications

References 54 publications

Recent advances in Echinococcus genomics and stem cell research

Recent advances in Echinococcus genomics and stem cell research

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part III: Helminths

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