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

Hulpia, Fabian; Mabille, Dorien; Campagnaro, Gustavo; Schumann, Gabriela; Maes, Louis; Roditi, Isabel; Hofer, Anders; de Koning, Harry; Caljon, Guy; Von Calenbergh, Serge (2019). Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness. Nature Communications, 10(1), p. 5564. Springer Nature 10.1038/s41467-019-13522-6

Preview

Text Hulpia_Mabille.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (1MB) | Preview

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.

Interest & Impact

Downloads

141 since deposited on 20 Jan 2020
16 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item