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Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors.


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.

SUBMITTER: Cho Y 

PROVIDER: S-EPMC3294498 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors.

Cho Yoonsang Y   Vermeire Jon J JJ   Merkel Jane S JS   Leng Lin L   Du Xin X   Bucala Richard R   Cappello Michael M   Lolis Elias E  

Chemistry & biology 20110901 9


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-throu  ...[more]

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