Repurposing Auranofin and Evaluation of a New Gold(I) Compound for the Search of Treatment of Human and Cattle Parasitic Diseases: From Protozoa to Helminth Infections

Abstract

Neglected parasitic diseases remain a major public health issue worldwide, especially in tropical and subtropical areas. Human parasite diversity is very large, ranging from protozoa to worms. In most cases, more effective and new drugs are urgently needed. Previous studies indicated that the gold(I) drug auranofin (Ridaura®) is effective against several parasites. Among new gold(I) complexes, the phosphole-containing gold(I) complex {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl (abbreviated as GoPI) is an irreversible inhibitor of both purified human glutathione and thioredoxin reductases. GoPI-sugar is a novel 1-thio-β-d-glucopyranose 2,3,4,6-tetraacetato-S-derivative that is a chimera of the structures of GoPI and auranofin, designed to improve stability and bioavailability of GoPI. These metal-ligand complexes are of particular interest because of their combined abilities to irreversibly target the essential dithiol/selenol catalytic pair of selenium-dependent thioredoxin reductase activity, and to kill cells from breast and brain tumors. In this work, screening of various parasites—protozoans, trematodes, and nematodes—was undertaken to determine the in vitro killing activity of GoPI-sugar compared to auranofin. GoPI-sugar was found to efficiently kill intramacrophagic Leishmania donovani amastigotes and adult filarial and trematode worms.

Repurposing of auranofin and honokiol as antifungals against Scedosporium species and the related fungus Lomentospora prolificans

“…Although TrxRs are likely the primary target of ARF, the exact mode of action of this drug is still disputable. Extensive studies reported its strong anti-parasitic activity, which correlates with a marked decrease in TrxR activity upon exposure to the drug, possibly because most parasites (i) lack the glutathione system or (ii) rely on a single TrxR for their antioxidant defense [19,24]. This is consistent with similar findings on bacteria since only species lacking the glutathione system were found susceptible [56].…”

“…Auranofin inhibits the HMW-TrxR via irreversible binding to its selenocysteinyl residue [16], but its inhibitory activity was also reported against LMW-TrxR lacking selenocysteine [17,18]. Therefore, it has been proposed for many infectious diseases, including bacterial, parasitic, and fungal infections [19][20][21][22][23][24]. In fungi, ARF demonstrated promising in vitro activity against several Candida species or Cryptococcus (Cr.)…”

Autonomous Non Antioxidant Roles for Fasciola hepatica Secreted Thioredoxin-1 and Peroxiredoxin-1

“…Comparative studies by Piedrafita et al (2000) on the susceptibility of F. hepatica and F. gigantica NEJs to killing by pro-inflammatory macrophages found a link between antioxidant expression and resistance. More recent studies have demonstrated the effectiveness of the TGR inhibitor gold (I) drug auranofin against several parasites, including schistosomes (Feng et al, 2020), that augurs well for the treatment of F. hepatica infection given that the single enzyme is pivotal to the whole cascade (Figure 1). The Trx1 and Prx1 enzymes may also be considered targets for vaccine-induced immune responses, either alone, together or in a cocktail with other antioxidants.…”

“…Similar investigations into the inhibition of F. gigantica TGR by auranofin determined that it is the interaction of the gold particle of auranofin with His571 of TGR that results in the inhibition of enzyme activity ( Kalita et al., 2018 ). The S. mansoni TGR was proposed as a tractable drug target due to the parasites’ inability to survive in the presence of auranofin ( Feng et al., 2020 ).…”

Identification of Promising Antifungal Drugs against Scedosporium and Lomentospora Species after Screening of Pathogen Box Library

“…The cytotoxicity of auranofin and iodoquinol is a key point for the use of these drugs in clinical settings for the treatment of fungal infections. In vitro analyses have already shown that cytotoxicity of auranofin varies significantly depending on the cell model, ranging from 0.15 to 6.38 µm [ 68 , 69 , 70 , 71 , 72 ]. However, since auranofin is a drug already used in humans to treat rheumatoid arthritis, it is important to consider the observations found in clinical trials.…”