Abstract
The L3-stage-specific chitinase OvCHT1 has been implicated in the development of Onchocerca volvulus, the causative agent of onchocerciasis. Closantel, a known anthelmintic drug, was previously discovered as a potent and specific OvCHT1 inhibitor. As closantel is also a known protonophore, we performed a simple scaffold modulation to map out the structural features that are relevant for its individual or dual biochemical roles. Furthermore, we present that either OvCHT1 inhibition or protonophoric activity was capable of affecting O. volvulus L3 molting and that the presence of both activities in a single molecule yielded more potent inhibition of the nematode's developmental process.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antinematodal Agents / therapeutic use*
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Caenorhabditis elegans / metabolism
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Chitinases / antagonists & inhibitors*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / therapeutic use*
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Ionophores / therapeutic use*
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Molting / drug effects
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Onchocerca volvulus / drug effects
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Onchocerca volvulus / growth & development*
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Onchocerciasis / drug therapy
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Salicylanilides / chemistry
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Salicylanilides / therapeutic use
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Structure-Activity Relationship
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Uncoupling Agents / therapeutic use
Substances
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Antinematodal Agents
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Enzyme Inhibitors
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Ionophores
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Salicylanilides
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Uncoupling Agents
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Chitinases
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closantel