On the molecular mechanism of chloroquine's antimalarial action

David J. Sullivan, Ilya Y. Gluzman, David G. Russell, Daniel E. Goldberg

Research output: Contribution to journalArticlepeer-review

Abstract

Chloroquine is thought to exert its antimalarial effect by preventing the polymerization of toxic heme released during proteolysis of hemoglobin in the Plasmodium digestive vacuole. The mechanism of this blockade has not been established. We incubated cultured parasites with subinhibitory doses of [3H] chloroquine and [3H]quinidine. These [3H]quinoline compounds became associated with hemozoin as assessed by electron microscope autoradiography and subcellular fractionation. In vitro, binding of [3H]quinoline inhibitors to the hemozoin chain depended on the addition of heme substrate. These data counter previous conclusions regarding the lack of quinoline association with hemozoin, explain the exaggerated accumulation of quinolines in the Plasmodium digestive vacuole, and suggest that a quinoline-heme complex incorporates into the growing polymer to terminate chain extension, blocking further sequestration of toxic heme.

Original languageEnglish (US)
Pages (from-to)11865-11870
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number21
DOIs
StatePublished - Oct 15 1996
Externally publishedYes

Keywords

  • Plasmodium
  • heme
  • hemozoin
  • histidine-rich protein

ASJC Scopus subject areas

  • General

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