Journal article
Identification and validation of tetracyclic benzothiazepines as plasmodium falciparum cytochrome bc 1 inhibitors
CK Dong, S Urgaonkar, JF Cortese, FJ Gamo, JF Garcia-Bustos, MJ Lafuente, V Patel, L Ross, BI Coleman, ER Derbyshire, CB Clish, AE Serrano, M Cromwell, RH Barker, JD Dvorin, MT Duraisingh, DF Wirth, J Clardy, R Mazitschek
Chemistry and Biology | CELL PRESS | Published : 2011
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 bc 1 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 bc 1 activity, an essential component of the parasite respiratory chain and target of the widely used antimalarial drug atovaquone, as the ..
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Awarded by National Science Foundation
Funding Acknowledgements
We thank Roger Wiegand, Ted Sybertz, and the members of the Broad Institute-Genzyme-MMV Malaria Drug Development Initiative for thoughtful discussions; Stuart Schreiber and the Broad Chemical Biology Program for access to key instrumentation and reagents; and Chris Johnson, Galina Beletsky, and Stephen Jonston for analytical support. This work was supported by grants from Medicines for Malaria Venture (to M.M.V.), The Broad Institute (SPARC), the NIH NICHD K12-HD000850 (to J.D.D.), the NSF Graduate Research Fellowship Program (to V.P.), the Harvard Malaria Initiative (to D.F.W.), and partial infrastructure supported by NIH-G12RR03051 (to A.E.S.)