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Open AccessFeature PaperArticle

Natural Sesquiterpene Lactones of the 4,15-iso-Atriplicolide Type are Inhibitors of Trypanothione Reductase

1
Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Corrensstraße 48, D-48149 Münster, Germany
2
Biochemie-Zentrum der Universität Heidelberg (BZH), Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(20), 3737; https://doi.org/10.3390/molecules24203737
Received: 30 September 2019 / Revised: 9 October 2019 / Accepted: 11 October 2019 / Published: 16 October 2019
In the course of our investigations on the antitrypanosomal potential of sesquiterpene lactones (STL), we have recently reported on the exceptionally strong activity of 4,15-iso-Atriplicolide tiglate, which demonstrated an IC50 value of 15 nM against Trypanosoma brucei rhodesiense, the etiologic agent responsible for East African human trypanosomiasis (HAT). Since STLs are known to often interact with their biological targets (e.g., in anti-inflammatory and anti-tumor activity) by means of the covalent modification of biological nucleophiles—most prominently free cysteine thiol groups in proteins—it was a straightforward assumption that such compounds might interfere with the trypanothione-associated detoxification system of trypanosomes. This system heavily relies on thiol groups in the form of the dithiol trypanothione (T(SH)2) and in the active centers of enzymes involved in trypanothione metabolism and homeostasis. Indeed, we found in the present study that 4,15-iso-atriplicolide tiglate, as well as its structural homologues, the corresponding methacrylate and isobutyrate, are inhibitors of trypanothione reductase (TR), the enzyme serving the parasites to keep T(SH)2 in the dithiol state. The TR inhibitory activity was demonstrated to be time-dependent and irreversible. Quite interestingly, of the several further STLs with different core structures that were also tested, none inhibited TR at a significant level. Thus, the TR inhibitory effect by the 4,15-iso-atriplicolide esters appears to be specific for this particular type of furanoheliangolide-type STL. Some structure–activity relationships can already be deduced on the basis of the data reported here, which may serve as the starting point for searching further, possibly more potent, TR inhibitors. View Full-Text
Keywords: sesquiterpene lactone; 4,15-iso-atriplicolide ester; Trypanosoma brucei; Trypanosoma cruzi; trypanothione reductase; irreversible inhibitor; antitrypanosomal activity sesquiterpene lactone; 4,15-iso-atriplicolide ester; Trypanosoma brucei; Trypanosoma cruzi; trypanothione reductase; irreversible inhibitor; antitrypanosomal activity
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MDPI and ACS Style

Lenz, M.; Krauth-Siegel, R.L.; Schmidt, T.J. Natural Sesquiterpene Lactones of the 4,15-iso-Atriplicolide Type are Inhibitors of Trypanothione Reductase. Molecules 2019, 24, 3737.

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