Schistosoma mansoni Sirtuins: Characterization and Potential as Chemotherapeutic Targets

dc.creatorLancelot, Julien
dc.creatorCaby, Stephanie
dc.creatorDubois-Abdesselem, Florence
dc.creatorVanderstraete, Mathieu
dc.creatorTrolet, Jacques
dc.creatorOliveira, Guilherme Corrêa de
dc.creatorBracher, Franz
dc.creatorJung, Manfred
dc.creatorPierce, Raymond John
dc.date2018-11-07T12:36:09Z
dc.date2018-11-07T12:36:09Z
dc.date2013
dc.date.accessioned2023-09-26T20:24:00Z
dc.date.available2023-09-26T20:24:00Z
dc.identifierLANCELOT, Julien et al. Schistosoma mansoni Sirtuins: Characterization and Potential as Chemotherapeutic Targets. PLoS Negl Trop Dis., v. 7, n. 9, e2428, 2013.
dc.identifier1935-2727
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/29916
dc.identifier10.1371/journal.pntd.0002428
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8856063
dc.descriptionBackground: The chemotherapy of schistosomiasis currently depends on the use of a single drug, praziquantel. In order to develop novel chemotherapeutic agents we are investigating enzymes involved in the epigenetic modification of chromatin. Sirtuins are dependent lysine deacetylases that are involved in a wide variety of cellular processes including histone deacetylation, and have been demonstrated to be therapeutic targets in various pathologies, including cancer. Methodology, Principal Findings: In order to determine whether Schistosoma mansoni sirtuins are potential therapeutic targets we first identified and characterized their protein sequences. Five sirtuins (SmSirt) are encoded in the S. mansoni genome and phylogenetic analysis showed that they are orthologues of mammalian Sirt1, Sirt2, Sirt5, Sirt6 and Sirt7. Both SmSirt1 and SmSirt7 have large insertion in the catalytic domain compared to their mammalian orthologues. SmSirt5 is the only mitochondrial sirtuin encoded in the parasite genome (orthologues of Sirt3 and Sirt4 are absent) and transcripts corresponding to at least five splicing isoforms were identified. All five sirtuins are expressed throughout the parasite life-cycle, but with distinct patterns of expression. Sirtuin inhibitors were used to treat both schistosomula and adult worms maintained in culture. Three inhibitors in particular, Sirtinol, Salermide and MS3 induced apoptosis and death of schistosomula, the separation of adult worm pairs, and a reduction in egg laying. Moreover, Salermide treatment led to a marked disruption of the morphology of ovaries and testes. Transcriptional knockdown of SmSirt1 by RNA interference in adult worms led to morphological changes in the ovaries characterized by a marked increase in mature oocytes, reiterating the effects of sirtuin inhibitors and suggesting that SmSirt1 is their principal target. Conclusion, Significance: Our data demonstrate the potential of schistosome sirtuins as therapeutic targets and validate screening for selective sirtuin inhibitors as a strategy for developing new drugs against schistosomiasis
dc.formatapplication/pdf
dc.languageeng
dc.publisherPublic Library of Science
dc.rightsopen access
dc.subjectEsquistossomose
dc.subjectdrogas
dc.subjectschistosomiasis
dc.subjectdrugs
dc.titleSchistosoma mansoni Sirtuins: Characterization and Potential as Chemotherapeutic Targets
dc.typeArticle


Este ítem pertenece a la siguiente institución