6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

Xingi, Evangelia; Smirlis, Despina; Myrianthopoulos, Vassilios; Magiatis, Prokopios; Grant, Karen M.; Meijer, Laurent; Mikros, Emmanuel; Skaltsounis, Alexios‐Léandros; Soteriadou, Ketty

doi:10.1016/j.ijpara.2009.04.005

Cited by 71 publications

(123 citation statements)

References 43 publications

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“…Compound 42 is our best lead compound, with an EC 50 on intracellular parasites of 60 Ϯ 5 nM and an SI of 50. Although several authors have already described the antileishmanial effect of indirubins (57)(58)(59), this particular derivative has not been previously tested on intracellular parasites. From previous published work, we already know some of the targets of the indirubins, such as Leishmania CRK3 or GSK3 (57,58).…”

Section: Discussionmentioning

confidence: 99%

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

Durieu

Prina

Olivier

et al. 2016

Antimicrob Agents Chemother

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h Existing therapies for leishmaniases present significant limitations, such as toxic side effects, and are rendered inefficient by parasite resistance. It is of utmost importance to develop novel drugs targeting Leishmania that take these two limitations into consideration. We thus chose a target-based approach using an exoprotein kinase, Leishmania casein kinase 1.2 (LmCK1.2) that was recently shown to be essential for intracellular parasite survival and infectivity. We developed a four-step pipeline to identify novel selective antileishmanial compounds. In step 1, we screened 5,018 compounds from kinase-biased libraries with Leishmania and mammalian CK1 in order to identify hit compounds and assess their specificity. For step 2, we selected 88 compounds among those with the lowest 50% inhibitory concentration to test their biological activity on host-free parasites using a resazurin reduction assay and on intramacrophagic amastigotes using a high content phenotypic assay. Only 75 compounds showed antileishmanial activity and were retained for step 3 to evaluate their toxicity against mouse macrophages and human cell lines. The four compounds that displayed a selectivity index above 10 were then assessed for their affinity to LmCK1.2 using a target deconvolution strategy in step 4. Finally, we retained two compounds, PP2 and compound 42, for which LmCK1.2 seems to be the primary target. Using this four-step pipeline, we identify from several thousand molecules, two lead compounds with a selective antileishmanial activity.

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Section: Discussionmentioning

confidence: 99%

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

Durieu

Prina

Olivier

et al. 2016

Antimicrob Agents Chemother

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“…Identification of P. falciparum gene homologue of GSK3β (PfGSK3β) (Droucheau et al 2004) has led to current efforts to exploit GSK3 (and other kinases) as a drug target for malaria. Homologues of GSK3 have also been identified in other Apicomplexan parasites, Leishmania donovani (Xingi et al 2009) and Trypanosoma brucei (Ojo et al 2008). Nurul Aiezzah et al (2010 was the first to report chemosuppressive effects of a GSK3 inhibitor (LiCl) in a murine model of malarial infection.…”

Section: Discussionmentioning

confidence: 99%

Anti-malarial and Anti-inflammatory Effects of Gynura procumbens are Mediated by Kaempferol via Inhibition of Glycogen Synthase Kinase-3β (GSK3β)

Sok

Lee

Sudi

et al. 2015

JSM

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“…Pencirian GSK-3 parasit menunjukkan bahawa terdapat perbezaan antara GSK-3 parasit dan manusia yang mencadangkan bahawa pengawalaturan GSK-3 parasit adalah berlainan daripada GSK-3 manusia. Selain itu, perlakuan perencat GSK-3 dalam kajian infeksi in vitro Trypanosoma brucei (Ojo et al 2008) dan Leishmania donovani (Xingi et al 2009) didapati mengganggu perkembangan parasit. Oleh itu, GSK-3 mempunyai potensi sebagai sasaran dadah terhadap parasit protozoa.…”

Section: Pengenalanunclassified

Pencirian Molekul Glikogen Sintase Kinase-3 daripada Eimeria tenella

Yao

Firdaus-Raih²,

Sidek³

et al. 2016

JSM

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The discovery of new anticoccidial drug targets is amongst the necessary efforts needed to control chicken coccidiosis caused by Eimeria species. In this study, the fragment coding for the putative Eimeria tenella glycogen synthase kinase-3 (GSK-3) was amplified from the cDNA of E. tenella. Homology search showed that generated E. tenella sequence has high similarities with sequences from other organisms. The conserved domains of and residues important for the activity were also predicted within the E. tenella GSK-3. Secondary structure analysis and homology modelling predicted that the protein structure is divided into a beta strand domain at the N terminal and an alpha helix domain at terminal C, which are characteristics of enzymes. These results supported the E. tenella GSK-3 codes for the protein in E. tenella. Although the degree of conservation is high, significant differences were observed between GSK-3 of E. tenella and its host. The Ser 9 residue reported to be important for the inhibition of the GSK-3 activity was not conserved within the E. tenella Considering that Ser 9 is a phosphorylation site in of vertebrates, the absence of this residue in the E. tenella GSK-3 sequence suggests that the regulation of E. tenella GSK-3 involves a different phosphorylation site and mechanism. Phylogenetic analysis suggests that E. tenella GSK-3 has a closer relationship to plant Superposition analysis between E. tenella GSK-3 and Homo sapiens predicted that E. tenella GSK-3 is able to interact with a GSK-3 inhibitor. Taken together, these results suggested that the E. tenella has the potential to be developed into an anticoccidial drug target.

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6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

Cited by 71 publications

References 43 publications

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

Anti-malarial and Anti-inflammatory Effects of Gynura procumbens are Mediated by Kaempferol via Inhibition of Glycogen Synthase Kinase-3β (GSK3β)

Pencirian Molekul Glikogen Sintase Kinase-3 daripada Eimeria tenella

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