Schistosoma mansoni Sirtuins: characterization and potential as chemotherapeutic targets.
Schistosoma mansoni Sirtuins: characterization and potential as chemotherapeutic targets.
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DOI：
10.1371/journal.pntd.0002428
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发表时间：
2013
影响因子：
3.8
通讯作者：
Pierce RJ
中科院分区：
文献类型：
--
作者：
Lancelot J;Caby S;Dubois-Abdesselem F;Vanderstraete M;Trolet J;Oliveira G;Bracher F;Jung M;Pierce RJ
血吸虫病的化疗目前依赖于吡喹酮这一单一药物的使用。为了开发新的化疗药物，我们正在研究参与染色质表观遗传修饰的酶。沉默调节蛋白是NAD+依赖性赖氨酸脱乙酰酶，其参与多种细胞过程，包括组蛋白脱乙酰化，并且已被证明是多种病理学（包括癌症）中的治疗靶标。为了确定曼氏血吸虫sirtuins是否是潜在的治疗靶点，我们首先鉴定并表征了它们的蛋白质序列。S. mansoni基因组和系统发育分析表明，它们与哺乳动物Sirt1、Sirt2、Sirt5、Sirt6和Sirt7同源。SmSirt1和SmSirt7都有大的插入在催化结构域相比，它们的哺乳动物直系同源物。SmSirt5是寄生虫基因组中编码的唯一线粒体sirtuin（不存在Sirt3和Sirt4的直系同源物），并且鉴定了对应于至少五种剪接异构体的转录物。所有五种sirtuins在整个寄生虫生命周期中表达，但具有不同的表达模式。Sirtuin抑制剂用于处理保持在培养物中的童虫和蠕虫。三种抑制剂，特别是，Sirtinol，Salermide和MS3诱导的细胞凋亡和死亡的童虫，成虫对的分离，并减少产卵。此外，Salermide给药导致卵巢和睾丸形态学明显破坏。RNA干扰在蠕虫中的SmSirt1的转录敲低导致卵巢的形态学变化，其特征在于成熟卵母细胞的显着增加，重申了沉默调节蛋白抑制剂的作用，并表明SmSirt1是其主要目标。我们的数据表明，作为治疗靶点，并验证选择性sirtuin抑制剂的筛选作为一种策略，开发新的药物，抗血吸虫病的潜在干扰体sirtuins。血吸虫病是一种由血吸虫属的寄生扁虫引起的疾病，影响热带和亚热带国家的2亿多人。目前对吡喹酮这一单一药物的依赖使得迫切需要开发新的治疗剂。我们选择的策略是靶向进行寄生虫染色质表观遗传修饰的酶，特别是组蛋白脱乙酰酶（HDAC）。HDAC的抑制剂已被开发为抗癌药物，我们的目标是利用在酶体的催化结构域的结构差异，以开发选择性抑制剂，将药物前体。Sirtuins是具有NAD+依赖性催化机制的组蛋白脱乙酰酶。在这项研究中，我们的特点是所有的曼氏血吸虫sirtuins，并表明它们在整个寄生虫的生命周期中表达。Sirtuin抑制剂可导致寄生虫幼虫死亡、成虫对分离和对蠕虫生殖器官的组织损伤。这些结果证明了S.作为治疗靶点的曼氏去乙酰化酶。
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 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. 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. 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. 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 current reliance on a single drug, Praziquantel, for the treatment and control of the disease renders urgent the development of new therapeutic agents. 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). Inhibitors of HDACs have been developed as drugs against cancer and our aim is to exploit structural differences in the catalytic domains of the schistosome enzymes in order to develop selective inhibitors that will be drug precursors. Sirtuins are histone deacetylases that have an NAD+-dependent catalytic mechanism. In this study we have characterized all the Schistosoma mansoni sirtuins and show that they are expressed throughout the parasite life-cycle. Sirtuin inhibitors cause the death of schistosome larvae, the separation of adult worm pairs and tissue damage to the worm reproductive organs. These results demonstrate the validity of S. mansoni sirtuins as therapeutic targets.
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影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
影响因子：
14.9
作者：
Cole C;Barber JD;Barton GJ
通讯作者：
Barton GJ
影响因子：
4.8
作者：
DAVIS, RE;HARDWICK, C;SINGH, H
通讯作者：
SINGH, H
DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
Frye, RA
通讯作者：
Frye, RA
影响因子：
2.9
作者：
Heltweg, B;Jung, M
通讯作者：
Jung, M