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

Gillan, V., O’Neill, K., Maitland, K., Sverdrup, F. M. and Devaney, E. (2014) A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes. PLoS Neglected Tropical Diseases, 8(2), e2699. (doi:10.1371/journal.pntd.0002699)

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Publisher's URL: http://dx.doi.org/10.1371/journal.pntd.0002699

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Devaney, Professor Eileen and Maitland, Ms Kirsty and Gillan, Dr Victoria
Authors: Gillan, V., O’Neill, K., Maitland, K., Sverdrup, F. M., and Devaney, E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:PLoS Neglected Tropical Diseases
Publisher:Public Library of Science
ISSN:1935-2727
ISSN (Online):1935-2735
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in PLoS Neglected Tropical Diseases 8(2):e2699
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
398951Hsp90 as a molecular target in lymphatic filariasisEileen DevaneyWellcome Trust (WELLCOME)076734/Z/05/ZIII - PARASITOLOGY
441591A comparative analysis of Hsp90 its possible role in drug resistance in nematode parasitesEileen DevaneyBiotechnology and Biological Sciences Research Council (BBSRC)BB/E013473/1III - PARASITOLOGY