Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery

Balaña‐Fouce, Rafael; Álvarez-Velilla, Raquel; Fernández-Prada, Christopher; Garcı́a-Estrada, Carlos; Reguera, Rosa M.

doi:10.1016/j.ijpddr.2014.07.006

Cited by 42 publications

(38 citation statements)

References 182 publications

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“…For all of the compounds except one the IC 50 was systematically higher against LmCK1.2 (0.44 to 2.4 M) than against mammalian CK1 (0.081 to 1.6 M). Only compound 26 had a lower IC 50 …”

Section: Resultsmentioning

confidence: 99%

“…This could suggest that the ATP binding pocket of SsCK1 could be more permissive than that of LmCK1.2. We selected 45 compounds either belonging to class 1 that inhibited LmCK1.2 activity by Ͼ90% or belonging to class 2 and were specific to LmCK1.2 to determine their IC 50 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Of the 45 compounds for which we determined the IC 50 , we selected two compounds with low IC 50 s but only moderate specificity toward LmCK1.2, purvalanol B, and indirubin-3=-monoxime, and we tested analog libraries to perform structure-activity relationship (SAR) analysis in order to identify more specific compounds. We chose purvalanol B because we showed previously that Leishmania CK1.2 binds to purvalanol B better than its mammalian counterpart, suggesting that the sensitivity to purvalanol B could be higher for LmCK1.2 than for SsCK1 (44).…”

Section: Resultsmentioning

confidence: 99%

“…We also excluded NSC699479 because of its weak affinity toward LmCK1.2, suggesting that this kinase might not be its primary target. Based on previous results in mammalian cells, the primary target of NSC699479 could be topoisomerases in Leishmania, enzymes already known as good drug targets (50,51,52).…”

Section: Discussionmentioning

confidence: 99%

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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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“…For all of the compounds except one the IC 50 was systematically higher against LmCK1.2 (0.44 to 2.4 M) than against mammalian CK1 (0.081 to 1.6 M). Only compound 26 had a lower IC 50 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…MB17 likely binds specifically to kinetoplast DNA, which results in the inhibition of DNA-dependent enzymes (10,11,31). Alternatively, MB17 may directly inhibit transcription and replication enzymes (11,31,(36)(37)(38). We propose that MB17 acts through its binding activity on the parasite DNA and not as a trypanocidal agent.…”

Section: Discussionmentioning

confidence: 91%

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

Girard

Crispim

Stolić

et al. 2016

Antimicrob Agents Chemother

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dTrypanosoma cruzi is the etiological agent of Chagas disease, affecting approximately 10 million people in the Americas and with some 40 million people at risk. The objective of this study was to evaluate the anti-T. cruzi activity of three new diamidines that have a 3,4-ethylenedioxy extension of the thiophene core, designated MB17, MB19, and MB38. All three diamidines exhibited dose-dependent inhibition of epimastigote replication. The mechanisms of action of these diamidines were investigated. Unlike MB17 and MB19, MB38 exhibited a significant increase in the number of annexin-propidium iodide double-labeled cells compared to levels in control parasites. As MB17 had shown a lower 50% inhibitory concentration (IC 50 ) against epimastigote growth, the mechanism of action of this drug was studied in more detail. MB17 triggered a decrease in the intracellular ATP levels. As a consequence, MB17 affected the genomic DNA and kinetoplast DNA (kDNA) and impaired the parasite cell cycle. Moreover, MB17 caused DNA fragmentation, with a more severe effect on kDNA than on nuclear DNA, resulting in dyskinetoplastic cells. MB17 was tested for toxicity and effectiveness for the treatment of infected CHO-K 1 cells, exhibiting a 50% cytotoxic concentration (CC 50 ) of 13.47 ؎ 0.37 M and an IC 50 of 0.14 ؎ 0.12 M against trypomastigote release. MB17 also diminished the infection index by 60% at 0.5 M. In conclusion, despite belonging to the same family, these diamidines have different efficiencies. To summarize, MB17 was the most potent of these diamidines against epimastigotes, producing DNA damage preferentially in kDNA, impairing the parasite cell cycle, and decreasing the infection index and trypomastigote release from infected mammalian host cells, with a high selectivity index (SI) (<90). These data suggest that MB17 could be an interesting lead compound against T. cruzi. A merican trypanosomiasis, or Chagas disease, affects approximately 10 million people, with 40 million people at risk of acquiring the infection. Chagas disease is endemic to South and Central America and the southern states of the United States. Currently, it is also spreading in Europe and the rest of North America due to the immigration of infected people, as well as through transmission of the disease by transfusions, transplants, and congenital mechanisms (1, 2). The disease is caused by the protozoan Trypanosoma cruzi, which shares some distinctive features with other trypanosomes, such as the presence of a flagellum and of a kinetoplast, a complex structure bearing the mitochondrial genome. In this case, the mitochondrial genomic DNA is referred to as kinetoplast DNA, or kDNA. It consists of a great number of relaxed circular DNA molecules interlocked with each other to form a catenated DNA network (3). T. cruzi has a complex life cycle, which occurs within invertebrate and vertebrate hosts (4-6). Chagas disease presents two clinical phases, the acute phase, which appears shortly after infection and is characterized by an evident parasitemia and ...

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In vitro trypanocidal activities and structure–activity relationships of ciprofloxacin analogs

Rensburg¹,

Suganuma²,

N’Da³

2023

Mol Divers

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Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery

Abstract: Graphical abstract

Cited by 42 publications

References 182 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

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

In vitro trypanocidal activities and structure–activity relationships of ciprofloxacin analogs

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