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Sci Rep. 2015 Sep 25;5:13891. doi: 10.1038/srep13891.

High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.

Author information

1
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
2
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
3
Department of Chemistry, Georgetown University, 37th and O St., NW, Washington, DC.
4
Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California, San Francisco, CA.
5
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
6
Department of Biochemistry, Cellular and Molecular Biology and Center for Infectious Diseases, Georgetown University, 37th and O St., NW, Washington, DC.

Abstract

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy.

PMID:
26403635
PMCID:
PMC4585899
DOI:
10.1038/srep13891
[Indexed for MEDLINE]
Free PMC Article

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