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Sci Rep. 2016 Jun 13;6:27806. doi: 10.1038/srep27806.

Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.

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  • 1Division of Pharmacology and Drug Discovery, Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, California, USA.
  • 2Department of Synthetic Biology and Bioenergy, J. Craig Venter Institute, La Jolla, California, USA.
  • 3Department of Chemistry &Biochemistry and the National Biomedical Computation Resource, University of California, San Diego, La Jolla, California, USA.
  • 4Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 5Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 6Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.


The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.

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