Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness

Hulpia, F., Mabille, D., Campagnaro, G. D., Schumann, G., Maes, L., Roditi, I., Hofer, A., De Koning, H. P. , Caljon, G. and Van Calenbergh, S. (2019) Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness. Nature Communications, 10, 5564. (doi: 10.1038/s41467-019-13522-6) (PMID:31804484) (PMCID:PMC6895180)

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Abstract

African trypanosomiasis is a disease caused by Trypanosoma brucei parasites with limited treatment options. Trypanosoma is unable to synthesize purines de novo and relies solely on their uptake and interconversion from the host, constituting purine nucleoside analogues a potential source of antitrypanosomal agents. Here we combine structural elements from known trypanocidal nucleoside analogues to develop a series of 3’-deoxy-7-deazaadenosine nucleosides, and investigate their effects against African trypanosomes. 3’-Deoxytubercidin is a highly potent trypanocide in vitro and displays curative activity in animal models of acute and CNS-stage disease, even at low doses and oral administration. Whole-genome RNAi screening reveals that the P2 nucleoside transporter and adenosine kinase are involved in the uptake and activation, respectively, of this analogue. This is confirmed by P1 and P2 transporter assays and nucleotide pool analysis. 3’-Deoxytubercidin is a promising lead to treat late-stage sleeping sickness.

Item Type:Articles
Additional Information:F.H. is indebted to the FWO-Flanders for a Ph.D. scholarship. G.D.C. thanks Science Without Borders for his scholarship (206385/2014-5, CNPq, Brazil). G.C. is supported by a research fund of the University of Antwerp (TT-ZAPBOF 33049). The present work has been funded by the FWO (G.C., L.M., S.V.C.; project number G013118N).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Campagnaro, Gustavo and De Koning, Professor Harry
Authors: Hulpia, F., Mabille, D., Campagnaro, G. D., Schumann, G., Maes, L., Roditi, I., Hofer, A., De Koning, H. P., Caljon, G., and Van Calenbergh, S.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Published Online:05 December 2019
Copyright Holders:Copyright © The Authors 2019
First Published:First published in Nature Communications 10:5564
Publisher Policy:Reproduced under a Creative Commons license

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