A Basis for Rapid Clearance of Circulating Ring-Stage Malaria Parasites by the Spiroindolone KAE609

J Infect Dis. 2016 Jan 1;213(1):100-4. doi: 10.1093/infdis/jiv358. Epub 2015 Jul 1.

Abstract

Recent clinical trials revealed a surprisingly rapid clearance of red blood cells (RBCs) infected with malaria parasites by the spiroindolone KAE609. Here, we show that ring-stage parasite-infected RBCs exposed to KAE609 become spherical and rigid, probably through osmotic dysregulation consequent to the disruption of the parasite's sodium efflux pump (adenosine triphosphate 4). We also show that this peculiar drug effect is likely to cause accelerated splenic clearance of the rheologically impaired Plasmodium vivax- and Plasmodium falciparum-infected RBCs.

Keywords: KAE609; Plasmodium falciparum; Plasmodium vivax; malaria; red blood cell; spiroindolones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / pharmacology*
  • Erythrocytes / parasitology
  • Humans
  • Indoles / pharmacology*
  • Malaria, Falciparum / parasitology*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics
  • Plasmodium vivax / drug effects*
  • Plasmodium vivax / genetics
  • Spiro Compounds / pharmacology*

Substances

  • Antimalarials
  • Indoles
  • NITD 609
  • Spiro Compounds