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. 2017 Sep 15;12(9):2354-2361.
doi: 10.1021/acschembio.7b00487. Epub 2017 Aug 16.

Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes

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Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes

Valerie J Winton et al. ACS Chem Biol. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
(a) UDP-galactopyranose mutase (UGM) catalyzes the interconversion of UDP-Galp and UDP-Galf. (b) Core structures of UGM small-molecule inhibitor scaffolds.
Figure 2
Figure 2
Modification of carboxylic acids by metabolic enzymes
Figure 3
Figure 3
A) Live C. elegans animals were counted after synchronization. All UGM inhibitors (100 µM) induced a statistically significant decrease in survival 48 hours following synchronization (* = p-value <0.05, ** = p-value <0.01, *** = p-value <0.005). B) Number of adults at 48 hours. Animals that survived late embryogenesis in the presence of compound 1 were healthy and developed normally. In contrast, animals treated with 2 or 4 were developmentally delayed. NGM: nematode growth medium
Figure 4
Figure 4
A) Representative images of C. elegans treated with compound 3 (25 µM) 48 hours after synchronization to the L1 stage, Scale bars are ~0.1 mm. B) C. elegans exposed to compound 3 (25 µM) were monitored for the Skd phenotype seen in mutants of cuticle glycosylation. C) Animals treated with compounds 1, 2, and 4 (50 µM) were assessed for their sensitivity to rupture in bleach (p-value <0.0001).

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