title: A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes.
abstract: Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties.
authors.affiliation: Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gillan
authors.affiliation: Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Kerry
authors.initials: K
authors.lastname: O'Neill
authors.affiliation: Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Maitland
authors.affiliation: Center for World Health & Medicine, Saint Louis University, Saint Louis, Missouri, United States of America.
authors.forename: Francis M
authors.initials: FM
authors.lastname: Sverdrup
authors.affiliation: Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Eileen
authors.initials: E
authors.lastname: Devaney
mesh_terms: D000818:Animals; D017179:Brugia pahangi / Q000187:drug effects*; D058492:Drug Repositioning; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005368:Filariasis / Q000469:parasitology*; D005369:Filaricides / Q000737:chemistry / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012118:Resorcinols / Q000494:pharmacology
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D004791:Enzyme Inhibitors; D005369:Filaricides; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D007555:Isoxazoles; D012118:Resorcinols