Bundschuh, Mirco
- Institutionen för vatten och miljö, Sveriges lantbruksuniversitet
- Rheinland-Pfälzische Technische Universität Kaiserslautern-Landau (RPTU)
Forskningsartikel2025Vetenskapligt granskad
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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Sammanfattning
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.
Nyckelord
African trypanosomiasis; Animal trypanosomiasis; drug discovery; nucleosideanalogues; mode of action; ecotoxicity
Publicerad i
ACS Infectious Diseases
2025, volym: 11, nummer: 1, sidor: 131-143
Utgivare: AMER CHEMICAL SOC
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UKÄ forskningsämne
Patobiologi
Publikationens identifierare
- DOI: https://doi.org/10.1021/acsinfecdis.4c00472
Permanent länk till denna sida (URI)
https://res.slu.se/id/publ/139856