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Targeting the substrate preference of a type I nitroreductase to develop anti-trypanosomal quinone-based prodrugs.

Hall, BS, Meredith, EL and Wilkinson, SR (2012) Targeting the substrate preference of a type I nitroreductase to develop anti-trypanosomal quinone-based prodrugs. Antimicrob Agents Chemother.

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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 (NTRs), enzymes found predominantly in prokaryotes. Based on flavin co-factor, oxygen-insensitive activity, substrate range and inhibition profiles, we demonstrate that NTR from T. cruzi and T. brucei display many characteristics of their bacterial counterparts. Intriguingly, both enzymes preferentially use NADH and quinones as 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 two-orders of magnitude greater than nifurtimox and benznidazole. When tested against T. brucei, anti-parasitic 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 unravelling the biochemical characteristics exhibited by the trypanosomal NTRs we have shown that quinone-based compounds represent a class of trypanocidal compound.

Item Type: Article
Authors :
NameEmailORCID
Hall, BSb.s.hall@surrey.ac.ukUNSPECIFIED
Meredith, ELUNSPECIFIEDUNSPECIFIED
Wilkinson, SRUNSPECIFIEDUNSPECIFIED
Date : 4 September 2012
Identification Number : https://doi.org/10.1128/AAC.01227-12
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:45
Last Modified : 17 May 2017 14:44
URI: http://epubs.surrey.ac.uk/id/eprint/825012

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