Discovery and Development of an Advanced Lead for the Treatment of African Trypanosomiasis
African trypanosomiasis is a widespread disease of human and veterinary importance caused by various <i>Trypanosoma spp.</i> 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 <i>in vitro</i> screening against the most relevant trypanosome species. Selected hit compounds were extensively tested for <i>in vitro</i> metabolic stability, potency in <i>in vivo</i> mouse models for the various species, genotoxicity in an <i>in vitro</i> testing battery, and mode of action studies (i.e., genome-wide RNA interference library screening and metabolomics). Among the nucleoside analogues, analogue <b>3</b> 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 <b>3</b> represents a potent, advanced lead fitting the preferred target product profile for a broad-spectrum trypanocide regardless of the causative species.
Authors
- Fabian Hulpia (ORCID: https://orcid.org/0000-0002-7470-3484)
- Dorien Mabille (ORCID: https://orcid.org/0000-0003-3530-0567)
- Harry P. de Koning (ORCID: https://orcid.org/0000-0002-9963-1827)
- An Matheeussen (ORCID: https://orcid.org/0000-0002-7507-1634)
- Louis Maes (ORCID: https://orcid.org/0000-0002-2324-9509)
- Clément Regnault (ORCID: https://orcid.org/0009-0002-2702-3707)
- Rik Hendrickx (ORCID: https://orcid.org/0000-0002-6751-4909)
- Rajdeep Roy (ORCID: https://orcid.org/0000-0001-5509-257X)
- Kayhan Ilbeigi (ORCID: https://orcid.org/0000-0003-2955-5096)
- Birgit Mertens (ORCID: https://orcid.org/0000-0001-8298-9104)
- Hans De Winter
- Yann G.‐J. Sterckx (ORCID: https://orcid.org/0000-0002-7420-0983)
- Phillip D. Whitfield (ORCID: https://orcid.org/0000-0002-0814-4119)
- Serge Van Calenbergh (ORCID: https://orcid.org/0000-0002-4201-1264)
- Roel Anthonissen
- Marzuq A. Ungogo (ORCID: https://orcid.org/0000-0003-4918-1423)
- Guy Caljon (ORCID: https://orcid.org/0000-0002-4870-3202)
- Mathieu Claes (ORCID: https://orcid.org/0000-0001-6396-0963)
- Nick Van Reet
- Mirco Bundschuh (ORCID: https://orcid.org/0000-0003-4876-220X)
- Cai Lin
Institutions
- University of Antwerp (BE)
- University of Koblenz and Landau (DE)
- Swedish University of Agricultural Sciences (SE)
- Ghent University (BE)
- OmniActive Health Technologies (United States) (US)
- Sciensano (Belgium) (BE)
- Instituut voor Tropische Geneeskunde (BE)
- University of Glasgow (GB)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2024-12-12
- DOI
- https://doi.org/10.1021/acsinfecdis.4c00472
- Citations
- 7
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- European Cooperation in Science and Technology
- Fonds Wetenschappelijk Onderzoek
- Universiteit Antwerpen