A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes

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 numero...

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Bibliographic Details
Published in:PLoS neglected tropical diseases 2014-02, Vol.8 (2), p.e2699-e2699
Main Authors: Gillan, Victoria, O'Neill, Kerry, Maitland, Kirsty, Sverdrup, Francis M, Devaney, Eileen
Format: Article
Language:English
Subjects:
Animals
Biology
Brugia pahangi - drug effects
Cancer
Cancer therapies
Care and treatment
Chemotherapy
Drug dosages
Drug Repositioning
Enzyme inhibitors
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Experiments
Female
Filariasis
Filariasis - parasitology
Filaricides - chemistry
Filaricides - pharmacology
Heat shock proteins
HSP90 Heat-Shock Proteins - antagonists & inhibitors
Humans
Infections
Isoxazoles - pharmacology
Male
Medicine
Mice
Mice, Inbred BALB C
Parasites
Parasitic diseases
Proteins
Resorcinols - pharmacology
Signal transduction
Studies
Tropical diseases
Worms
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Summary: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.
ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0002699