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Cynaropicrin targets the trypanothione redox system in Trypanosoma brucei.
Bioorg Med Chem. 2013 Nov 15; 21(22):7202-9.BM

Abstract

In mice cynaropicrin (CYN) potently inhibits the proliferation of Trypanosoma brucei-the causative agent of Human African Trypanosomiasis-by a so far unknown mechanism. We hypothesized that CYNs α,β-unsaturated methylene moieties act as Michael acceptors for glutathione (GSH) and trypanothione (T(SH)2), the main low molecular mass thiols essential for unique redox metabolism of these parasites. The analysis of this putative mechanism and the effects of CYN on enzymes of the T(SH)2 redox metabolism including trypanothione reductase, trypanothione synthetase, glutathione-S-transferase, and ornithine decarboxylase are shown. A two step extraction protocol with subsequent UPLC-MS/MS analysis was established to quantify intra-cellular CYN, T(SH)2, GSH, as well as GS-CYN and T(S-CYN)2 adducts in intact T. b. rhodesiense cells. Within minutes of exposure to CYN, the cellular GSH and T(SH)2 pools were entirely depleted, and the parasites entered an apoptotic stage and died. CYN also showed inhibition of the ornithine decarboxylase similar to the positive control eflornithine. Significant interactions with the other enzymes involved in the T(SH)2 redox metabolism were not observed. Alongside many other biological activities sesquiterpene lactones including CYN have shown antitrypanosomal effects, which have been postulated to be linked to formation of Michael adducts with cellular nucleophiles. Here the interaction of CYN with biological thiols in a cellular system in general, and with trypanosomal T(SH)2 redox metabolism in particular, thus offering a molecular explanation for the antitrypanosomal activity is demonstrated. At the same time, the study provides a novel extraction and analysis protocol for components of the trypanosomal thiol metabolism.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24080104

Citation

Zimmermann, Stefanie, et al. "Cynaropicrin Targets the Trypanothione Redox System in Trypanosoma Brucei." Bioorganic & Medicinal Chemistry, vol. 21, no. 22, 2013, pp. 7202-9.
Zimmermann S, Oufir M, Leroux A, et al. Cynaropicrin targets the trypanothione redox system in Trypanosoma brucei. Bioorg Med Chem. 2013;21(22):7202-9.
Zimmermann, S., Oufir, M., Leroux, A., Krauth-Siegel, R. L., Becker, K., Kaiser, M., Brun, R., Hamburger, M., & Adams, M. (2013). Cynaropicrin targets the trypanothione redox system in Trypanosoma brucei. Bioorganic & Medicinal Chemistry, 21(22), 7202-9. https://doi.org/10.1016/j.bmc.2013.08.052
Zimmermann S, et al. Cynaropicrin Targets the Trypanothione Redox System in Trypanosoma Brucei. Bioorg Med Chem. 2013 Nov 15;21(22):7202-9. PubMed PMID: 24080104.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cynaropicrin targets the trypanothione redox system in Trypanosoma brucei. AU - Zimmermann,Stefanie, AU - Oufir,Mouhssin, AU - Leroux,Alejandro, AU - Krauth-Siegel,R Luise, AU - Becker,Katja, AU - Kaiser,Marcel, AU - Brun,Reto, AU - Hamburger,Matthias, AU - Adams,Michael, Y1 - 2013/09/05/ PY - 2013/06/14/received PY - 2013/08/16/revised PY - 2013/08/23/accepted PY - 2013/10/2/entrez PY - 2013/10/2/pubmed PY - 2014/5/16/medline KW - CYN KW - DMFO KW - DTT KW - Drug target KW - FA KW - GSH KW - HAT KW - HPLC–MS/MS KW - Human African Trypanosomiasis KW - IS KW - LLOD KW - LLOQ KW - ODC KW - SAR KW - SS KW - STL KW - Sesquiterpene lactone KW - SpS KW - T(SH)(2) KW - TR KW - TryS KW - Trypanosoma brucei KW - Trypanothione KW - cynaropicrin KW - dithiothreitol KW - eflornithine KW - formic acid KW - glutathione KW - internal standard KW - lower limit of detection KW - lower limit of quantification KW - ornithine decarboxylase KW - sesquiterpene lactone KW - spermidine synthase KW - stock solution KW - structure activity relationship KW - trypanothione KW - trypanothione reductase KW - trypanothione synthetase SP - 7202 EP - 9 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 21 IS - 22 N2 - In mice cynaropicrin (CYN) potently inhibits the proliferation of Trypanosoma brucei-the causative agent of Human African Trypanosomiasis-by a so far unknown mechanism. We hypothesized that CYNs α,β-unsaturated methylene moieties act as Michael acceptors for glutathione (GSH) and trypanothione (T(SH)2), the main low molecular mass thiols essential for unique redox metabolism of these parasites. The analysis of this putative mechanism and the effects of CYN on enzymes of the T(SH)2 redox metabolism including trypanothione reductase, trypanothione synthetase, glutathione-S-transferase, and ornithine decarboxylase are shown. A two step extraction protocol with subsequent UPLC-MS/MS analysis was established to quantify intra-cellular CYN, T(SH)2, GSH, as well as GS-CYN and T(S-CYN)2 adducts in intact T. b. rhodesiense cells. Within minutes of exposure to CYN, the cellular GSH and T(SH)2 pools were entirely depleted, and the parasites entered an apoptotic stage and died. CYN also showed inhibition of the ornithine decarboxylase similar to the positive control eflornithine. Significant interactions with the other enzymes involved in the T(SH)2 redox metabolism were not observed. Alongside many other biological activities sesquiterpene lactones including CYN have shown antitrypanosomal effects, which have been postulated to be linked to formation of Michael adducts with cellular nucleophiles. Here the interaction of CYN with biological thiols in a cellular system in general, and with trypanosomal T(SH)2 redox metabolism in particular, thus offering a molecular explanation for the antitrypanosomal activity is demonstrated. At the same time, the study provides a novel extraction and analysis protocol for components of the trypanosomal thiol metabolism. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/24080104/Cynaropicrin_targets_the_trypanothione_redox_system_in_Trypanosoma_brucei_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(13)00755-4 DB - PRIME DP - Unbound Medicine ER -