| Affiliation: | 1Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, MA 02115, USA;2Infectious Diseases Initiative, Broad Institute, Cambridge, MA 02142, USA;3Metabolite Profiling Initiative, Broad Institute, Cambridge, MA 02142, USA;4Diseases of the Developing World (DDW), GlaxoSmithKline R&D, Tres Cantos, Madrid 28760, Spain;5Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA;6Department of Microbiology and Medical Zoology, School of Medicine, University of Puerto Rico, San Juan 00936-5067, Puerto Rico;7Drug and Biomaterial R&D, Genzyme Corporation, Waltham, MA 02451, USA;8Division of Infectious Diseases, Children's Hospital Boston, Boston, MA 02115, USA;9Center for Systems Biology, Massachusetts General Hospital, Boston MA 02114, USA |
| Abstract: | Here we report the discovery of tetracyclic benzothiazepines (BTZs) as highly potent and selective antimalarials along with the identification of the Plasmodium falciparum cytochrome bc1 complex as the primary functional target of this novel compound class. Investigation of the structure activity relationship within this previously unexplored chemical scaffold has yielded inhibitors with low nanomolar activity. A combined approach employing genetically modified parasites, biochemical profiling, and resistance selection validated inhibition of cytochrome bc1 activity, an essential component of the parasite respiratory chain and target of the widely used antimalarial drug atovaquone, as the mode of action of this novel compound class. Resistance to atovaquone is eroding the efficacy of this widely used antimalarial drug. Intriguingly, BTZ-based inhibitors retain activity against atovaquone resistant parasites, suggesting this chemical class may provide an alternative to atovaquone in combination therapy. |
