Discussion
Animal trypanosomiasis (AT) is a widespread disease caused by
Trypanosoma spp. and has a devastating effect on animal husbandry all over the world due to the scarcity of efficient drugs and development of drug resistance, hence emphasizing the need for novel treatment options. Following previous identification of 3’-deoxytubercidin as a highly potent trypanocide with curative activity in mouse models of both stage-1 and stage-2 Human African Trypanosomiasis (HAT), we now present a comprehensive preclinical evaluation of new 6-amino substituted tubercidin analogues with promising activity against a broad range of AT species. Potent hits were identified
in vitro across all important AT species,
i.e. T. b. brucei, sensitive and isometamidium (ISM)-resistant
T. congolense,
T. vivax,
T. evansi (type A and B) and
T. equiperdum. Selected ‘hits’ were further tested for
in vitro metabolic stability (using bovine, horse and piglet liver microsomes),
in vivo mouse models for each AT species, genotoxicity assays and mode-of-action studies (
i.e. genome-wide RNA interference library screening, metabolomics). Analogue
3 was highly active in
T. vivax,
T. congolense,
T. equiperdum,
T. evansi and
T. brucei curative mouse models. Furthermore, there was no indication of
in vitro genotoxicity as confirmed by Vitotox®, the micronucleus and the comet assays. Mode-of-action studies for
3 revealed that the P1 nucleoside transporter and adenosine kinase are involved in drug uptake and activation, respectively. Given the preferred target product profile for a broad-spectrum drug against AT, analogue
3 represents a promising ‘lead’ candidate for treatment of animal trypanosomiasis, regardless of the causative species.
Animal trypanosomiasis | drug discovery | nucleoside analogues | RNAi
