Abstract
BackgroundThe 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 NAD+ 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 FindingsIn 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, SignificanceOur 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.
Highlights
The current strategy for the treatment and control of schistosomiasis is the mass-treatment of populations in endemic areas using the only available drug, Praziquantel
Schistosomiasis is a disease affecting more than 200 million people in tropical and sub-tropical countries caused by parasitic flatworms of the genus Schistosoma
The strategy that we have chosen is to target the enzymes that carry out epigenetic modifications of the chromatin in the parasite and in particular the histone deacetylases (HDACs)
Summary
The current strategy for the treatment and control of schistosomiasis is the mass-treatment of populations in endemic areas using the only available drug, Praziquantel. We have chosen to target a group of enzymes that is under active study for the development of anti-cancer drugs, the enzymes that effect posttranslational modifications of histones including the (de)acetylation and (de)methylation of lysine or arginine residues. Inhibitors of these enzymes have been shown to be generally more toxic for cancer cells than for normal cells [6]. Sirtuins are NAD+ 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
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