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Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 5564Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 10, article id 5564
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Pharmacology and Toxicology
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URN: urn:nbn:se:umu:diva-167057DOI: 10.1038/s41467-019-13522-6ISI: 000502059600001PubMedID: 31804484OAI: oai:DiVA.org:umu-167057DiVA, id: diva2:1384067
Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-09Bibliographically approved

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Mabille, DorienRoditi, IsabelHofer, Andersde Koning, Harry P.Van Calenbergh, Serge
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