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.

17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice

“…In protozoan parasites, the protein has been reported to regulate the cellular processes in zoonotic protozoan parasites such as Plasmodium , Toxoplasma , Trypanosoma, and Leishmania ( Banumathy et al, 2003 ; Angel et al, 2013 ). Furthermore, several studies have shown the effectiveness of Hsp90 as drug target for infectious diseases ( Pizarro et al, 2013 ; Gillan et al, 2014 ).…”

Hsp90 Inhibitors in Parasitic Nematodes: Prospects and Challenges

“…For example, our recent work demonstrated that filarial worms were killed by in vitro exposure to 25.0 nM NVP-AUY922 and showed that this compound was also active in vivo against adult worms [54]. While our studies have focused largely on B. pahangi, we, and others [21], have shown similar effects on the human pathogen to transport imaging reagents into tumors [56[57].…”

“…A number of other chemical scaffolds including purine-scaffold and isoxazole-based compounds have now been tested against filarial worms with various levels of activity [43,54]. For example, our recent work demonstrated that filarial worms were killed by in vitro exposure to 25.0 nM NVP-AUY922 and showed that this compound was also active in vivo against adult worms [54].…”

Nematode Hsp90: highly conserved but functionally diverse

“…In more recent work from this laboratory, we examined whether Hsp90 inhibitors might affect adult worms in vivo (Gillan et al . 2014). For this purpose we selected an isoxazole inhibitor, NVP-AUY922, which had previously been demonstrated to exhibit anti-tumour activity in a mouse xenograft tumour model (Eccles et al 2008; Garon et al 2013).…”