Abstract
The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a "proof-of-concept" for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Ancylostomatoidea / drug effects
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Ancylostomatoidea / metabolism*
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Binding Sites
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Catalytic Domain
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Crystallography, X-Ray
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Diuretics / chemistry
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Diuretics / pharmacology
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Diuretics / therapeutic use
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Drug Repositioning*
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Furosemide / chemistry
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Furosemide / pharmacology
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Furosemide / therapeutic use
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High-Throughput Screening Assays
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Hookworm Infections / drug therapy
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Humans
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Kinetics
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Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
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Macrophage Migration-Inhibitory Factors / genetics
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Macrophage Migration-Inhibitory Factors / metabolism
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Meclofenamic Acid / chemistry
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Meclofenamic Acid / pharmacology
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Meclofenamic Acid / therapeutic use
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Small Molecule Libraries / therapeutic use
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Diuretics
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Macrophage Migration-Inhibitory Factors
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Small Molecule Libraries
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Meclofenamic Acid
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Furosemide