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Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes
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posted on 2017-07-21, 00:00 authored by Valerie
J. Winton, Alexander M. Justen, Helen Deng, Laura L. KiesslingParasitic 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.