ArticleAntimicrobial agents and chemotherapy2012
Targeting the substrate preference of a type I nitroreductase to develop antitrypanosomal quinone-based prodrugs.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 34 citations in OpenAlex.
- Advances and challenges in the search for new treatments for Chagas disease.Memorias do Instituto Oswaldo Cruz · 2026Review
- The Catalysis Mechanism ofInternational journal of molecular sciences · 2024Article
- Anti-Molecules (Basel, Switzerland) · 2023Article
- Heterologous Expression and Characterization of a Full-length Protozoan Nitroreductase from Leishmania orientalis isolate PCM2.Molecular biotechnology · 2023Article
- Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity.International journal of molecular sciences · 2021Review
- New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story.Tropical medicine and infectious disease · 2020Review
- Old Yellow Enzyme fromFrontiers in immunology · 2018Article
- Hypoxia-activated prodrugs and redox-responsive nanocarriers.International journal of nanomedicine · 2018Review
- Distinct activation mechanisms trigger the trypanocidal activity of DNA damaging prodrugs.Molecular microbiology · 2017Article
- Identification of a type I nitroreductase gene in non-virulent Trypanosoma rangeli.Memorias do Instituto Oswaldo Cruz · 2017Article
- Nitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activity.European journal of medicinal chemistry · 2016Article
- Antitrypanosomal activity of 5-nitro-2-aminothiazole-based compounds.European journal of medicinal chemistry · 2016Article
- Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism.Antimicrobial agents and chemotherapy · 2016Article
- Comparative characterisation of two nitroreductases from Giardia lamblia as potential activators of nitro compounds.International journal for parasitology. Drugs and drug resistance · 2015Article
- Novel 3-nitrotriazole-based amides and carbinols as bifunctional antichagasic agents.Journal of medicinal chemistry · 2015Article
- An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs.The Journal of biological chemistry · 2013Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Nitroheterocyclic prodrugs are used to treat infections caused by Trypanosoma cruzi and Trypanosoma brucei. A key component in selectivity involves a specific activation step mediated by a protein homologous with type I nitroreductases, enzymes found predominantly in prokaryotes. Using data from determinations based on flavin cofactor, oxygen-insensitive activity, substrate range, and inhibition profiles, we demonstrate that NTRs from T. cruzi and T. brucei display many characteristics of their bacterial counterparts. Intriguingly, both enzymes preferentially use NADH and quinones as the electron donor and acceptor, respectively, suggesting that they may function as NADH:ubiquinone oxidoreductases in the parasite mitochondrion. We exploited this preference to determine the trypanocidal activity of a library of aziridinyl benzoquinones against bloodstream-form T. brucei. Biochemical screens using recombinant NTR demonstrated that several quinones were effective substrates for the parasite enzyme, having K(cat)/K(m) values 2 orders of magnitude greater than those of nifurtimox and benznidazole. In tests against T. brucei, antiparasitic activity mirrored the biochemical data, with the most potent compounds generally being preferred enzyme substrates. Trypanocidal activity was shown to be NTR dependent, as parasites with elevated levels of this enzyme were hypersensitive to the aziridinyl agent. By unraveling the biochemical characteristics exhibited by the trypanosomal NTRs, we have shown that quinone-based compounds represent a class of trypanocidal compound.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.