Several Schistosoma species cause Schistosomiasis, an endemic disease in 78 countries that is ranked second amongst the parasitic diseases in terms of its socioeconomic impact and human health importance. The drug recommended for treatment by the WHO is praziquantel (PZQ), but there are concerns associated with PZQ, such as the lack of information about its exact mechanism of action, its high price, its effectiveness — which is limited to the parasite's adult form — and reports of resistance. The parasites lack the de novo purine pathway, rendering them dependent on the purine salvage pathway or host purine bases for nucleotide synthesis. Thus, the Schistosoma purine salvage pathway is an attractive target for the development of necessary and selective new drugs. In this study, the purine nucleotide phosphorylase II (PNP2), a new isoform of PNP1, was submitted to a high-throughput fragment-based hit discovery using a crystallographic screening strategy. PNP2 was crystallized and crystals were soaked with 827 fragments, a subset of the Maybridge 1000 library. X-ray diffraction data was collected and structures were solved. Out of 827-screened fragments we have obtained a total of 19 fragments that show binding to PNP2. Fourteen of these fragments bind to the active site of PNP2, while five were observed in three other sites. Here we present the first fragment screening against PNP2.

中文翻译：

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基于片段的针对曼氏血吸虫嘌呤核苷磷酸化酶的命中发现的晶体学方法

几种血吸虫物种引起血吸虫病，这是一种在 78 个国家/地区的地方病，就其社会经济影响和人类健康重要性而言，在寄生虫病中排名第二。世卫组织推荐用于治疗的药物是吡喹酮 (PZQ)，但存在与 PZQ 相关的担忧，例如缺乏有关其确切作用机制、价格高昂、有效性的信息——仅限于寄生虫的成虫形式- 和抵抗报告。寄生虫缺乏从头嘌呤途径，使它们依赖于嘌呤补救途径或宿主嘌呤碱基进行核苷酸合成。因此，血吸虫嘌呤补救途径是开发必要和选择性新药的有吸引力的目标。在这项研究中，嘌呤核苷酸磷酸化酶 II (PNP2)，一种新的 PNP1 同种型被提交给使用晶体筛选策略的基于高通量片段的命中发现。PNP2 被结晶，晶体被 827 个片段浸泡，这是 Maybridge 1000 库的一个子集。收集X射线衍射数据并解析结构。在筛选出的 827 个片段中，我们总共获得了 19 个显示与 PNP2 结合的片段。这些片段中有 14 个与 PNP2 的活性位点结合，而在其他三个位点观察到了 5 个。在这里，我们展示了针对 PNP2 的第一个片段筛选。在筛选出的 827 个片段中，我们总共获得了 19 个显示与 PNP2 结合的片段。这些片段中有 14 个与 PNP2 的活性位点结合，而在其他三个位点观察到了 5 个。在这里，我们展示了针对 PNP2 的第一个片段筛选。在筛选出的 827 个片段中，我们总共获得了 19 个显示与 PNP2 结合的片段。这些片段中有 14 个与 PNP2 的活性位点结合，而在其他三个位点观察到了 5 个。在这里，我们展示了针对 PNP2 的第一个片段筛选。