title: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yoonsang
authors.initials: Y
authors.lastname: Cho
authors.forename: Jon J
authors.initials: JJ
authors.lastname: Vermeire
authors.forename: Jane S
authors.initials: JS
authors.lastname: Merkel
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Michael
authors.initials: M
authors.lastname: Cappello
authors.forename: Elias
authors.initials: E
authors.lastname: Lolis
mesh_terms: D000723:Ancylostomatoidea / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004232:Diuretics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D058492:Drug Repositioning; D005665:Furosemide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D057166:High-Throughput Screening Assays; D006725:Hookworm Infections / Q000188:drug therapy; D006801:Humans; D007700:Kinetics; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008469:Meclofenamic Acid / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004232:Diuretics; D008263:Macrophage Migration-Inhibitory Factors; D054852:Small Molecule Libraries; D008469:Meclofenamic Acid; D005665:Furosemide