2. Academic Validation
  3. The Thienopyrimidinone Gamhépathiopine Targets the QO Site of Plasmodium falciparum Cytochrome b

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

  • ACS Infect Dis. 2025 Jun 13;11(6):1719-1728. doi: 10.1021/acsinfecdis.5c00259.
Natalie Wiedemar 1,  Rachel Milne 1,  Sandra Carvalho 1,  Stephen Patterson 1,  Mike Bodkin 2,  Nicolas Masurier 3,  Vincent Lisowski 3 4,  Nicolas Primas 5 6,  Pierre Verhaeghe 7 8,  Graeme M Sloan 2,  Susan Wyllie 1
Affiliations

Affiliations

  • 1 Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.
  • 2 Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.
  • 3 Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques, 34093 Montpellier, France.
  • 4 Department of Pharmacy, Lapeyronie Hospital, CHU Montpellier, 191 Av. du Doyen Gaston Giraud, 34295 Montpellier, France.
  • 5 AP-HM, Service Central de la Qualité et de l'Information Pharmaceutiques, Hôpital Conception, 13005 Marseille, France.
  • 6 Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille, France.
  • 7 LCC-CNRS Université de Toulouse, CNRS, UPS, 31062 Toulouse, France.
  • 8 Université de Grenoble Alpes, CNRS, DPM UMR 5063, 38041 Grenoble, France.
PMID: 40460517 DOI: 10.1021/acsinfecdis.5c00259
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.

Keywords

Qo active site; cytochrome b; drug discovery; malaria; mode of action; thienopyrimidinone.

Figures
Products