A Novel Antiparasitic Compound Kills Ring-Stage Plasmodium falciparum and Retains Activity Against Artemisinin-Resistant Parasites

Abstract Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory conce...

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Bibliographic Details
Published in:The Journal of infectious diseases 2020-03, Vol.221 (6), p.956-962
Main Authors: Clements, Rebecca L, Streva, Vincent, Dumoulin, Peter, Huang, Weigang, Owens, Edward, Raj, Dipak K, Burleigh, Barbara, Llinás, Manuel, Winzeler, Elizabeth A, Zhang, Qisheng, Dvorin, Jeffrey D
Format: Article
Language:English
Subjects:
Antimalarial agents
Antimalarials - administration & dosage
Antimalarials - chemistry
Antimalarials - pharmacology
Antiparasitic agents
Artemisinin
Artemisinins - pharmacology
Cells, Cultured
Drug Resistance
Erythrocytes
Fibroblasts - parasitology
Humans
Infectious diseases
Major and Brief Reports
Malaria
Metabolomics
Molecular Structure
Parasite resistance
Parasites
Plasmodium falciparum
Plasmodium falciparum - drug effects
Structure-Activity Relationship
Trophozoites
Trypanosoma cruzi - drug effects
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Summary:Abstract Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory concentration [IC50] = 1–2 µM), suggesting that BCH070 acts via a novel mechanism of action. BCH070 preferentially kills early ring-form trophozoites, and, importantly, equally inhibits ring-stage survival of wild-type and artemisinin-resistant parasites harboring the PfKelch13:C580Y mutation. Metabolomic analysis demonstrates that BCH070 likely targets multiple pathways in the parasite. BCH070 is a promising lead compound for development of new antimalarial combination therapy that retains activity against artemisinin-resistant parasites. BCH070 inhibits growth of antimalarial-resistant strains of Plasmodium falciparum, including artemisinin-resistant parasites. BCH070 is active during a unique life-cycle stage, likely targeting multiple parasite pathways. Thus, BCH070 is a strong lead candidate in the development of novel antimalarial combination therapy.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiz534