Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31.
Identification and activity of inhibitors of the essential nematode-specific metalloprotease DPY-31.
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DOI：
10.1016/j.bmcl.2015.10.077
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发表时间：
2015-12-15
影响因子：
2.7
通讯作者：
Page AP
中科院分区：
文献类型：
--
作者：
France DJ;Stepek G;Houston DR;Williams L;McCormack G;Walkinshaw MD;Page AP
寄生线虫的感染在发展中国家很普遍，造成广泛的发病率和死亡率。此外，动物感染是一个全球性问题，对粮食生产产生重大影响。在这里，我们确定小分子抑制剂的线虫特异性金属蛋白酶，DPY-31，使用已知的金属蛋白酶抑制剂和虚拟筛选。该策略成功地从人丝虫马来丝虫和绵羊Teladorsagia circumcincta的寄生性胃肠道线虫中鉴定出几种μM DPY-31抑制剂。使用自由生活和寄生线虫的进一步研究表明，这些抑制剂引起严重的身体形态缺陷“矮胖”（Dpy;更短和更胖），一种主要的非存活表型，与缺乏DPY-31基因的突变体一致。总之，这些结果代表了开发DPY-31抑制作为治疗人类和动物寄生线虫感染的全新机制的起点。
Infection by parasitic nematodes is widespread in the developing world causing extensive morbidity and mortality. Furthermore, infection of animals is a global problem, with a substantial impact on food production. Here we identify small molecule inhibitors of a nematode-specific metalloprotease, DPY-31, using both known metalloprotease inhibitors and virtual screening. This strategy successfully identified several μM inhibitors of DPY-31 from both the human filarial nematode Brugia malayi, and the parasitic gastrointestinal nematode of sheep Teladorsagia circumcincta. Further studies using both free living and parasitic nematodes show that these inhibitors elicit the severe body morphology defect ‘Dumpy’ (Dpy; shorter and fatter), a predominantly non-viable phenotype consistent with mutants lacking the DPY-31 gene. Taken together, these results represent a start point in developing DPY-31 inhibition as a totally novel mechanism for treating infection by parasitic nematodes in humans and animals.