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DOI: 10.1055/s-0035-1565479
4,15-Isoatriplicolide-esters: new inhibitors of trypanothione reductase
The sesquiterpene lactone 4,15-isoatriplicolide tiglate 1 was recently discovered as an extremely potent trypanocidal agent with an in vitro IC50 of only 15 nM against Trypanosoma brucei rhodesiense, causative pathogen of East African Human Trypanosomiasis (HAT) [1]. Trypanosomatids possess a unique mechanism to maintain their redox state and defend themselves against oxidative stress, in which the glutathione/glutathione reductase system, serving this purpose in other Eukaryotes, is replaced by Trypanothione/Trypanothione reductase (TR). TR is therefore a potential target for new leads and drugs against HAT and related diseases [2]. In an attempt to identify potential molecular targets of the isoatriplicolide ester in trypanosomes, we have investigated the possibility that it inhibits the parasites' most crucial redox enzyme.
In vitro studies with T. cruzi (Tc) and T. brucei (Tb) TR have clearly shown that the enzyme is inhibited to variable extent by the tiglate 1 as well as the corresponding methacrylate 2 and isobutyrate 3; Under the chosen assay conditions [2], e.g. 20, 40 and 100 µM of 1 inhibited the Tc enzyme enzyme by 52, 71 and 89% after only 15 min pre-incubation. Time dependent inhibition experiments with the Tb enzyme furthermore indicate that the enzyme is inhibited in an irreversible manner. This observation may point towards a covalent modification in the enzymes' active site which contains two cysteine residues with essential function in the catalytic mechanism [3]. Further studies aiming at a full characterization of the inhibition mechanism are in progress.
Acknowledgements: This work is part of the activities of ResNetNPND (http://www. ResNetNPND.org/) and was performed as a cooperation within COST action CM1307.
References:
[1] Schmidt T J et al., Antimicrob. Agents Chemother. 2014; 58, 325 – 332.
[2] Persch E et al., Chem. Med. Chem. 2014, 9; 1880 – 1891.
[3] Fairlamb AH, Cerami A. Annu. Rev. Microbiol. 1992; 46, 695 – 729.