Planta Med 2015; 81 - PM_102
DOI: 10.1055/s-0035-1565479

4,15-Isoatriplicolide-esters: new inhibitors of trypanothione reductase

M Lenz 1, L Krauth-Siegel 2, TJ Schmidt 1
  • 1University of Münster Institute of Pharmaceutical Biology and Phytochemistry PharmaCampus, Corrensstrasse 48, Münster, Germany
  • 2Biochemie-Zentrum der Universität Heidelberg (BZH), Im Neuenheimer Feld 328, Heidelberg, Germany

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.

Fig. 1: Structures of 4,15-isoatriplicolide esters 1 – 3

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.