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Research article2025Peer reviewed

Discovery and Development of an Advanced Lead for the Treatment of African Trypanosomiasis

Ilbeigi, Kayhan; Mabille, Dorien; Matheeussen, An; Hendrickx, Rik; Claes, Mathieu; Van Reet, Nick; Anthonissen, Roel; Hulpia, Fabian; Lin, Cai; Maes, Louis; Regnault, Clement; Whitfield, Phillip; Roy, Rajdeep; Ungogo, Marzuq A.; Sterckx, Yann G. -J.; De Winter, Hans; Mertens, Birgit; Bundschuh, Mirco; De Koning, Harry P.; Van Calenbergh, Serge;
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Abstract

African trypanosomiasis is a widespread disease of human and veterinary importance caused by various Trypanosoma spp. with a globally devastating impact and a need for novel treatment options. We here provide a comprehensive preclinical evaluation of nucleoside analogues, 6-thioether-modified tubercidins, with curative activity against African trypanosomiasis. Promising hits were identified following in vitro screening against the most relevant trypanosome species. Selected hit compounds were extensively tested for in vitro metabolic stability, potency in in vivo mouse models for the various species, genotoxicity in an in vitro testing battery, and mode of action studies (i.e., genome-wide RNA interference library screening and metabolomics). Among the nucleoside analogues, analogue 3 was curative in mouse models with no indication of genotoxicity and a low ecotoxicological footprint. Mode-of-action studies revealed that P1-type nucleoside transporters and adenosine kinase are involved in the uptake and activation, respectively. Analogue 3 represents a potent, advanced lead fitting the preferred target product profile for a broad-spectrum trypanocide regardless of the causative species.

Keywords

African trypanosomiasis; Animal trypanosomiasis; drug discovery; nucleosideanalogues; mode of action; ecotoxicity

Published in

ACS Infectious Diseases
2025, volume: 11, number: 1, pages: 131-143
Publisher: AMER CHEMICAL SOC

SLU Authors

UKÄ Subject classification

Pathobiology

Publication identifier

  • DOI: https://doi.org/10.1021/acsinfecdis.4c00472

Permanent link to this page (URI)

https://res.slu.se/id/publ/139856