ArticleAmino acids2012
A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition.
Article in Amino acids, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 181 citations in OpenAlex.
- Beyond the Active Site: First-In-Class Leishmania Infantum Trypanothione Reductase Dimerization Disruptors as Antileishmanial Leads.ChemMedChem · 2026Review
- Structural basis of ligand selectivity in FAD/NAD(P)H-dependent dehydrogenases: insights from trypanothione reductase and type II NADH dehydrogenase.Protein science : a publication of the Protein Society · 2026Article
- Mechanism of auranofin toxicity: Inhibition of tetrahydrobiopterin metabolism.Toxicology and applied pharmacology · 2026Article
- Repurposing Auranofin for Oncology and Beyond: A Brief Overview of Clinical Trials as Mono- and Combination Therapy.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Targeting Trypanothione Synthetase and Trypanothione Reductase: Development of Common Inhibitors to Tackle Trypanosomatid Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma.Cancer biology & medicine · 2025Article
- Functional utility of gold complexes with phosphorus donor ligands in biological systems.Coordination chemistry reviews · 2025Article
- 1,2,4-Oxadiazole Derivatives: Physicochemical Properties, Antileishmanial Potential, Docking and Molecular Dynamic Simulations ofMolecules (Basel, Switzerland) · 2024Article
- Innovating Leishmaniasis Treatment: A Critical Chemist's Review of Inorganic Nanomaterials.ACS infectious diseases · 2024Review
- Targeting Trypanothione Metabolism in Trypanosomatids.Molecules (Basel, Switzerland) · 2024Review
- Study of metalation of thioredoxin by gold(I) therapeutic compounds using combined liquid chromatography/capillary electrophoresis with inductively coupled plasma/electrospray MS/MS detection.Analytical and bioanalytical chemistry · 2024Article
- Gold(I) and Silver(I) Complexes Containing Hybrid Sulfonamide/Thiourea Ligands as Potential Leishmanicidal Agents.Pharmaceutics · 2024Article
- Gold(I) ion and the phosphine ligand are necessary for the anti-Microbiology spectrum · 2024Article
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- Triose Phosphate Isomerase Structure-Based Virtual Screening and In Vitro Biological Activity of Natural Products asPharmaceutics · 2023Article
- Next Generation Gold Drugs and Probes: Chemistry and Biomedical Applications.Chemical reviews · 2023Review
- Structure ofInternational journal of molecular sciences · 2023Article
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- Novel gold(III)-dithiocarbamate complex targeting bacterial thioredoxin reductase: antimicrobial activity, synergy, toxicity, and mechanistic insights.Frontiers in microbiology · 2023Article
6 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin-trypanothione reductase-NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis.
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