The Thienopyrimidinone Gamhépathiopine Targets the QO Site of Plasmodium falciparum Cytochrome b

Chemotherapy remains a key component of the
arsenal of tools to fight malaria. Specifically, new drugs with diverse
mechanism(s) of action are required to combat existing drug
resistance. Here, we describe comprehensive studies to determine
the molecular target(s) of gamhépathiopine, a thienopyrimidinone
showing promise for the treatment of malaria. In vitro evolution of
gamhépathiopine resistance and whole genome analyses identified
mutations within the QO site of Plasmodium falciparum cytochrome
b, part of complex III of the electron transport chain. Subsequent
biochemical assays demonstrated that gamhépathiopine directly
inhibits complex III activity. Furthermore, exogenous expression of
Saccharomyces cerevisiae dihydroorotate dehydrogenase, known to
render the electron transport chain dispensable in Plasmodium,
results in complete abrogation of gamhépathiopine activity. Cross-resistance profiling and docking studies indicate that
gamhépathiopine occupies a similar, but not identical, binding pose to the established QO-targeting antimalarial atovaquone. The
implications of these findings for the future development of gamhépathiopine are discussed.