Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alveolar echinococcosis (AE), caused by the metacestode larval stage of the fox-tapeworm Echinococcus multilocularis, is a life-threatening disease with very limited treatment options. In search for novel drug targets, we concentrate on factors of the cellular signaling machinery and report herein the characterization of a novel gene, Emmpk2, which is expressed in the parasite's larval stage and which codes for a member of the mitogen-activated protein kinase (MAPK) family. On the amino acid sequence level, the encoded protein, EmMPK2, shares considerable homologies with p38 MAPKs from a wide variety of animal organisms but also displays several distinct differences, particularly in amino acid residues known to be involved in the regulation of enzyme activity. Upon heterologous expression in Escherichia coli, purified EmMPK2 showed prominent autophosphorylation activity and strongly elevated basal activity towards a MAPK substrate, when compared to the closest human orthologue, p38-alpha. EmMPK2 activity could be effectively inhibited in the presence of ML3403 and SB202190, two ATP-competitive pyridinyl imidazole inhibitors of p38 MAPKs, in a concentration-dependent manner. When added to in vitro cultivated metacestode vesicles, SB202190 and particularly ML3403 led to dephosphorylation of EmMPK2 in the parasite and effectively killed parasite vesicles at concentrations that did not affect cultivated mammalian cells. Taken together, these results identify pyridinyl imidazoles as a novel class of anti-Echinococcus compounds and EmMPK2 as a promising target for the development of drugs against alveolar echinococcosis.
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PMID:Characterization and inhibition of a p38-like mitogen-activated protein kinase (MAPK) from Echinococcus multilocularis: antiparasitic activities of p38 MAPK inhibitors. 1878 2

Alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is a lethal disease in humans. Novel therapeutic options are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. In this study, we assessed the in vitro and in vivo effects of the epidermal growth factor receptor (EGFR)/MEK/extracellular signal-regulated kinase (ERK) signaling inhibitors, including BIBW2992, CI-1033, and U0126, on E. multilocularis Our data showed that BIBW2992, CI-1033, and U0126 all displayed in vitro effects on the viability of the E. multilocularis metacestode. These inhibitors also showed protoscolicidal activities and caused severe ultrastructural alterations in the parasite. Moreover, BIBW2992 and CI-1033 exhibited potent proapoptotic effects on E. multilocularis metacestodes. Strikingly, a large portion of the apoptotic cells were found to be the germinative cells. In vivo studies showed that BIBW2992 and U0126 significantly reduced parasite burden, and the parasite obtained from BIBW2992-treated mice displayed impaired structural integrity of the germinal layer. In conclusion, these findings demonstrate the potential of EGFR-mediated signaling as a target for the development of novel anti-AE agents. The EGFR inhibitor BIBW2992 represents a promising drug candidate and/or a lead compound for anti-AE chemotherapy.
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PMID:In Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis. 3248 75