The mode of action of suramin on the filarial worm <i>Brugia pahangi</i>

Howells, R. E.; Mendis, A. M.; Bray, Patrick G.

doi:10.1017/s0031182000052392

Cited by 22 publications

(12 citation statements)

References 12 publications

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“…Additionally, previous studies with suramin, one of the few compounds with activity against adult filarial worms, demonstrated that it took approximately 6 weeks to reduce adult worm recovery in the jird model [39]. A total of eight out of 48 transplanted female worms were recovered from drug treated animals, but of these only two were healthy with the others being coated in cells, indicating that they were in the process of being cleared by the immune system.…”

Section: Discussionmentioning

confidence: 98%

A Repurposing Strategy for Hsp90 Inhibitors Demonstrates Their Potency against Filarial Nematodes

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 98%

A Repurposing Strategy for Hsp90 Inhibitors Demonstrates Their Potency against Filarial Nematodes

et al. 2014

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“…In part, this may reflect issues related to the uptake of drug by adult worms. At least in vitro , it is probable that small molecules are taken up across the cuticle [49], while in vivo the intestine is functional [50]. Little is known of the factors that influence the permeability of the filarial cuticle to small molecules.…”

Section: Discussionmentioning

confidence: 99%

Assay Strategies for the Discovery and Validation of Therapeutics Targeting Brugia pahangi Hsp90

et al. 2010

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The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target.

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“…A second example involves use of suramin against filarial nematodes (Howells et al, 1983) in which the anthelmintic effect was attributed to activity against the intestine, producing ultrastructural changes. Notably, the timeframe for efficacy extended to 5 weeks posttreatment, indicating survival for a prolonged period despite apparent intestinal tissue damage.…”

Section: The Nematode Intestine As a Target For New Anthelmintic Thermentioning

confidence: 99%

Omics Driven Understanding of the Intestines of Parasitic Nematodes

et al. 2019

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The biological and molecular complexity of nematodes has impeded research on development of new therapies for treatment and control. We have focused on the versatility of the nematode intestine as a target for new therapies. To that end, it is desirable to establish a broad and deep understanding of the molecular architecture underlying intestinal cell functions at the pan-Nematoda level. Multiomics data were generated to uncover the evolutionary principles underlying both conserved and adaptable features of the nematode intestine. Whole genomes were used to reveal the functional potential of the nematodes, tissue-specific transcriptomes provided a deep assessment of genes that are expressed in the adult nematode intestine, and comparison of selected core species was used to determine a first approximation of the pan-Nematoda intestinal transcriptome. Differentially expressed transcripts were also identified among intestinal regions, with the largest number expressed at significantly higher levels in the anterior region, identifying this region as the most functionally unique compared to middle and posterior regions. Profiling intestinal miRNAs targeting these genes identified the conserved intestinal miRNAs. Proteomics of intestinal cell compartments assigned proteins to several different intestinal cell compartments (intestinal tissue, the integral and peripheral intestinal membranes, and the intestinal lumen). Finally, advanced bioinformatic approaches were used to predict intestinal cell functional categories of seminal importance to parasite survival, which can now be experimentally tested and validated. The data provide the most comprehensive compilation of constitutively and differentially expressed genes, predicted gene regulators, and proteins of the nematode intestine. The information provides knowledge that is essential to understand molecular features of nematode intestinal cells and functions of fundamental importance to the intestine of many, if not all, parasitic nematodes.

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The mode of action of suramin on the filarial worm Brugia pahangi

Cited by 22 publications

References 12 publications

A Repurposing Strategy for Hsp90 Inhibitors Demonstrates Their Potency against Filarial Nematodes

A Repurposing Strategy for Hsp90 Inhibitors Demonstrates Their Potency against Filarial Nematodes

Assay Strategies for the Discovery and Validation of Therapeutics Targeting Brugia pahangi Hsp90

Omics Driven Understanding of the Intestines of Parasitic Nematodes

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