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) (PMID:24551261) (PMCID:PMC3923716)
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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 |
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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 > School of Biodiversity, One Health & Veterinary 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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