New uses for old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhibits potent antimalarial effects in vitro: Mechanistic and pharmacological implications

Abstract

The clinically established gold-based antiarthritic drug auranofin (AF) manifests a pronounced reactivity toward thiol and selenol groups of proteins. In particular, AF behaves as a potent inhibitor of mammalian thioredoxin reductases causing severe intracellular oxidative stress. Given the high sensitivity of Plasmodium falciparum to oxidative stress, we thought that auranofin might act as an effective antimalarial agent. Thus, we report here new experimental results showing that auranofin and a few related gold complexes strongly inhibit P. falciparum growth in vitro. The observed antiplasmodial effects probably arise from direct inhibition of P. falciparum thioredoxin reductase. The above findings and the safe toxicity profile of auranofin warrant rapid evaluation of AF for malaria treatment in animal models.

Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi , the Agent of Chagas' Disease

“…To address enormous unmet medical needs, there have been recent efforts in "repurposing" drugs (14,15,45,55) from other therapies even for neglected parasitic diseases (5,8,19,27,34,38,39). The current therapeutic drugs for Chagas' (13).…”

Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration

“…Also, AF was found to react directly with several thiol-redox enzymes such as thioredoxin reductase (Cox et al, 2008;Gandin et al, 2010;Rigobello et al, 2004) and glutathione-S-transferase (De Luca et al, 2013), that are most likely involved in the mediation of its anti-parasitic and antimicrobial effects (Angelucci et al, 2009;Sannella et al, 2008). Furthermore, in some bacterial strains, AF was found to inhibit selenoprotein synthesis .…”

In VitroEffects of Novel Ruthenium Complexes in Neospora caninum and Toxoplasma gondii Tachyzoites

“…This has stimulated the interest in other compounds with more acceptable toxicity, such as ruthenium complexes (32)(33)(34)(35)(36). Effects of ruthenium compounds on some bacteria and parasites have been studied (37)(38)(39)(40)(41)(42)(43)(44)(45)(46). "Classical ruthenium complexes" contain heteroatom ligands (e.g., azole derivatives), and NAMI-A and KP-1019 have been evaluated in phase I clinical trials for cancer treatment (47)(48)(49).…”

“…7A and B) form parasitophorous vacuoles containing proliferating tachyzoites. In cultures treated with compound 16, the drug rapidly induced a Parasite proliferation was assessed by measuring ␤-galactosidase activity (23,24,45), and HFF cell vitality was assessed by alamarBlue assay (38). b IC 50 s are given in nM for parasites and in M for HFF.…”