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

Fabian Hulpia, Dorien Mabille, Gustavo D. Campagnaro, Gabriela Schumann, Louis Maes, Isabel Roditi, Anders Hofer, Harry P. de Koning, Guy Caljon and Serge Van Calenbergh ()
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Fabian Hulpia: Ghent University
Dorien Mabille: University of Antwerp
Gustavo D. Campagnaro: University of Glasgow
Gabriela Schumann: University of Bern
Louis Maes: University of Antwerp
Isabel Roditi: University of Bern
Anders Hofer: Umeå University
Harry P. de Koning: University of Glasgow
Guy Caljon: University of Antwerp
Serge Van Calenbergh: Ghent University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13522-6

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