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

[img]
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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Biology > Institute of Cell Biology

UniBE Contributor:

Schumann-Burkard, Gabriela Eva and Roditi, Isabel

Subjects:

500 Science > 570 Life sciences; biology

ISSN:

2041-1723

Publisher:

Springer Nature

Language:

English

Submitter:

Isabel Roditi

Date Deposited:

20 Jan 2020 10:45

Last Modified:

26 Jan 2020 02:50

Publisher DOI:

10.1038/s41467-019-13522-6

PubMed ID:

31804484

BORIS DOI:

10.7892/boris.138642

URI:

https://boris.unibe.ch/id/eprint/138642

Actions (login required)

Edit item Edit item
Provide Feedback