Isobenzofuranone derivative JVPH3, an inhibitor of L. donovani topoisomerase II, disrupts mitochondrial architecture in trypanosomatid parasites
| العنوان: | Isobenzofuranone derivative JVPH3, an inhibitor of L. donovani topoisomerase II, disrupts mitochondrial architecture in trypanosomatid parasites |
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| المؤلفون: | Joseane Lima Prado Godinho, Parasuraman Jaisankar, Jayaraman Vinayagam, Sara Teixeira de Macedo Silva, Hemanta K. Majumder, Aline Araujo Zuma, Juliany Cola Fernandes Rodrigues, Somenath Roy Chowdhury, Wanderley de Souza |
| المصدر: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018) |
| بيانات النشر: | Nature Publishing Group UK, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Trypanosoma cruzi, Population, Leishmania donovani, lcsh:Medicine, Apoptosis, Mitochondrion, Article, 03 medical and health sciences, Microscopy, Electron, Transmission, Organelle, parasitic diseases, Topoisomerase II Inhibitors, Mode of action, education, lcsh:Science, Leishmania, education.field_of_study, Multidisciplinary, biology, DNA, Kinetoplast, lcsh:R, biology.organism_classification, Molecular biology, Mitochondria, 030104 developmental biology, DNA Topoisomerases, Type II, Kinetoplast, Biocatalysis, Microscopy, Electron, Scanning, lcsh:Q |
| الوصف: | Kinetoplast DNA (kDNA) bearing unusual mitochondrion of trypanosomatid parasites offers a new paradigm in chemotherapy modality. Topoisomerase II of Leishmania donovani (LdTopII), a key enzyme associated with kDNA replication, is emerging as a potential drug target. However, mode of action of LdTopII targeted compounds in the parasites at sub-cellular level remains largely unknown. Previously, we reported that an isobenzofuranone derivative, namely 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3), targets LdTopII and induces apoptosis-like cell death in L. donovani. Here, we elucidate the phenotypic changes and the events occurring at sub-cellular level caused by JVPH3 in L. donovani. In addition, we have evaluated the cytotoxicity and ultrastructural alterations caused by JVPH3 in two brazilian trypanosomatid pathogens viz. L. amazonensis and Trypanosoma cruzi. Despite killing these parasites, JVPH3 caused significantly different phenotypes in L. donovani and L. amazonensis. More than 90% population of parasites showed altered morphology. Mitochondrion was a major target organelle subsequently causing kinetoplast network disorganization in Leishmania. Altered mitochondrial architecture was evident in 75–80% Leishmania population being investigated. Quantification of mitochondrial function using JC-1 fluorophore to measure a possible mitochondrial membrane depolarization further confirmed the mitochondrion as an essential target of the JVPH3 corroborating with the phenotype observed by electron microscopy. However, the impact of JVPH3 was lesser on T. cruzi than Leishmania. The molecule caused mitochondrial alteration in 40% population of the epimastigotes being investigated. To our knowledge, this is the first report to evaluate the proliferation pattern and ultrastructural alterations caused in Brazilian kinetoplastid pathogens by a synthetic LdTopII inhibitor previously established to have promising in vivo activity against Indian strain of L. donovani. |
| اللغة: | English |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::633b73781ac61dd3a0dd874841846979 http://europepmc.org/articles/PMC6085290 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....633b73781ac61dd3a0dd874841846979 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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