Identification and Validation of Tetracyclic Benzothiazepines as Plasmodium falciparum Cytochrome bc1 Inhibitors
| Autor: | Adelfa E. Serrano, Jeffrey D. Dvorin, Emily R. Derbyshire, Clary B. Clish, Ralph Mazitschek, Carolyn K. Dong, Jon Clardy, Robert H. Barker, Jose F. Garcia-Bustos, Manoj T. Duraisingh, Vishal Patel, Maria Jose Lafuente, Leila S. Ross, Joseph F. Cortese, Bradley I. Coleman, Sameer Urgaonkar, Mandy Cromwell, Francisco-Javier Gamo, Dyann F. Wirth |
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| Rok vydání: | 2011 |
| Předmět: |
Drug
Cytochrome Thiazepines media_common.quotation_subject Molecular Sequence Data Plasmodium falciparum Clinical Biochemistry Respiratory chain Pharmacology Biochemistry Article Antimalarials Electron Transport Complex III Mice Structure-Activity Relationship 03 medical and health sciences Parasitic Sensitivity Tests Drug Discovery medicine Animals Structure–activity relationship Binding site Molecular Biology Atovaquone 030304 developmental biology media_common 0303 health sciences Binding Sites biology 030306 microbiology Cytochrome bc1 Reproducibility of Results General Medicine biology.organism_classification Protein Structure Tertiary 3. Good health Mutation biology.protein Molecular Medicine medicine.drug |
| Zdroj: | Chemistry & Biology. 18(12):1602-1610 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2011.09.016 |
| Popis: | SummaryHere 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. |
| Databáze: | OpenAIRE |
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