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

## TL;DR

This paper identifies how a new malaria drug candidate works by targeting a specific site in the malaria parasite's energy-producing system.

## Contribution

The study reveals that gamhépathiopine inhibits Plasmodium falciparum cytochrome b at the QO site, offering a novel mechanism for antimalarial drugs.

## Key findings

- Gamhépathiopine resistance is linked to mutations in the QO site of cytochrome b.
- Gamhépathiopine directly inhibits complex III activity in the electron transport chain.
- The drug's binding site is similar but distinct from atovaquone.

## Abstract

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.