Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes,ACS Chemical Biology

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Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-08-16 00:00:00 , DOI: 10.1021/acschembio.7b00487
Valerie J. Winton ₁ , Alexander M. Justen ₂ , Helen Deng ₂ , Laura L. Kiessling _{1,

2}

Affiliation

Parasitic nematodes pose a serious threat to agriculture, livestock, and human health. Increasing resistance to antiparasitic agents underscores the need to replenish our anthelmintic arsenal. The nonpathogenic Caenorhabditis elegans, which serves as an effective model of parasitic helminths, has been used to search for new anthelmintic leads. We previously reported small-molecule inhibitors of the essential C. elegans protein UDP-galactopyranose mutase (UGM or Glf). This enzyme is required for the generation of galactofuranose (Galf)-containing glycans and is needed in nematodes for proper cuticle formation. Though our first-generation inhibitors were effective in vitro, they elicited no phenotypic effects. These findings are consistent with the known difficulty of targeting nematodes. C. elegans is recalcitrant to pharmacological modulation; typically, less than 0.02% of small molecules elicit a phenotypic effect, even at 40 μM. We postulated that the lack of activity of the UGM inhibitors was due to their carboxylic acid group, which can be exploited by nematodes for detoxification. We therefore tested whether replacement of the carboxylate with an N-acylsulfonamide surrogate would result in active compounds. UGM inhibitors with the carboxylate mimetic can phenocopy the deleterious consequences of UGM depletion in C. elegans. These findings support the use of UGM inhibitors as anthelmintic agents. They also outline a strategy to render small-molecule carboxylates more effective against nematodes.

中文翻译：

线虫的UDP-半乳糖苷酶突变抑制的有害后果

寄生线虫对农业，畜牧业和人类健康构成了严重威胁。对抗寄生虫药的抵抗力的增强凸显了补充我们的驱虫药库的需要。非致病性秀丽隐杆线虫可作为寄生虫蠕虫的有效模型，已被用于寻找新的驱虫药线索。我们以前报道了必需的秀丽隐杆线虫蛋白UDP-吡喃半乳糖突变酶（UGM或Glf）的小分子抑制剂。该酶是产生含半乳糖呋喃糖（Gal f）的聚糖所必需的，而在线虫中也需要该酶以适当地形成角质层。虽然我们的第一代抑制剂在体外有效，他们没有引起表型效应。这些发现与靶向线虫的已知困难一致。秀丽隐杆线虫对药理学调节是顽固的；通常，即使在40μM的情况下，不到0.02％的小分子会引发表型效应。我们推测，UGM抑制剂缺乏活性是由于其羧酸基团，线虫可以利用其羧基进行解毒。因此，我们测试了用N-酰基磺酰胺替代物取代羧酸盐是否会产生活性化合物。具有羧酸盐模拟物的UGM抑制剂可以表型化秀丽隐杆线虫中UGM耗竭的有害后果。这些发现支持使用UGM抑制剂作为驱虫药。他们还概述了使小分子羧酸盐更有效地对抗线虫的策略。

更新日期：2017-08-16

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