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

Abstract

African trypanosomiasis is a widespread disease of human and veterinary importance caused by variouswith 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 followingscreening against the most relevant trypanosome species. Selected hit compounds were extensively tested formetabolic stability, potency inmouse models for the various species, genotoxicity in antesting battery, and mode of action studies (i.e., genome-wide RNA interference library screening and metabolomics). Among the nucleoside analogues, analoguewas 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. Analoguerepresents a potent, advanced lead fitting the preferred target product profile for a broad-spectrum trypanocide regardless of the causative species.