Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model

Animal
African trypanosomiasis (AAT) is a significant socioeconomic
burden for sub-Saharan Africa because of its huge impact on livestock
health. Existing therapies including those based on minor groove binders
(MGBs), such as the diamidines, which have been used for decades,
have now lost efficacy in some places because of the emergence of
resistant parasites. Consequently, the need for new chemotherapies
is urgent. Here, we describe a structurally distinct class of MGBs,
Strathclyde MGBs (S-MGBs), which display excellent in vitro activities
against the principal causative organisms of AAT: Trypanosoma
congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we
identify S-MGB-234, compound 7, as curative
by using two applications of 50 mg/kg intraperitoneally. Crucially,
we demonstrate that S-MGBs do not show cross-resistance with the current
diamidine drugs and are not internalized via the transporters used
by diamidines. This study demonstrates that S-MGBs have significant
potential as novel therapeutic agents for AAT.