A new approach to chemotherapy: drug-induced differentiation kills African trypanosomes

Wenzler, Tanja; Schumann-Burkard, Gabriela; Schmidt, Remo S.; Mäser, Pascal; Bergner, Andreas; Roditi, Isabel; Brun, Reto (2016). A new approach to chemotherapy: drug-induced differentiation kills African trypanosomes. Scientific Reports, 6(22451), p. 22451. Nature Publishing Group 10.1038/srep22451

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Human African trypanosomiasis (sleeping sickness) is a neglected tropical disease caused by Trypanosoma brucei spp. The parasites are transmitted by tsetse flies and adapt to their different hosts and environments by undergoing a series of developmental changes. During differentiation, the trypanosome alters its protein coat. Bloodstream form trypanosomes in humans have a coat of variant surface glycoprotein (VSG) that shields them from the immune system. The procyclic form, the first life-cycle stage to develop in the tsetse fly, replaces the VSG coat by procyclins; these proteins do not protect the parasite from lysis by serum components. Our study exploits the parasite-specific process of differentiation from bloodstream to procyclic forms to screen for potential drug candidates. Using transgenic trypanosomes with a reporter gene in a procyclin locus, we established a whole-cell assay for differentiation in a medium-throughput format. We screened 7,495 drug-like compounds and identified 28 hits that induced expression of the reporter and loss of VSG at concentrations in the low micromolar range. Small molecules that induce differentiation to procyclic forms could facilitate studies on the regulation of differentiation as well as serving as scaffolds for medicinal chemistry for new treatments for 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 and Roditi, Isabel

Subjects:

500 Science > 570 Life sciences; biology

ISSN:

2045-2322

Publisher:

Nature Publishing Group

Funders:

[UNSPECIFIED] Bill and Melinda Gates Foundation
[UNSPECIFIED] Howard Hughes Medical Institute

Language:

English

Submitter:

Isabel Roditi

Date Deposited:

11 Mar 2016 09:22

Last Modified:

26 Jun 2016 02:07

Publisher DOI:

10.1038/srep22451

PubMed ID:

26931380

BORIS DOI:

10.7892/boris.72275

URI:

https://boris.unibe.ch/id/eprint/72275

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