Revealing Chloroquine's Antimalarial Mechanism: The Suppression of Nucleation Events during Heme to Hemozoin Transformation

Abstract

Malaria parasites generate toxic heme during hemoglobin digestion, which is neutralized by crystallizing into inert hemozoin ({beta}-hematin). Chloroquine blocks this detoxification process, resulting in heme-mediated toxicity in malaria parasites. However, the exact mechanism of chloroquines action remains unknown. This study investigates the impact of chloroquine on the transformation of heme into {beta}-hematin. The results show that chloroquine does not completely halt the transformation process but rather slows it down. Additionally, chloroquine complexation with free heme does not affect substrate availability or inhibit {beta}-hematin formation. SEM and XRD studies indicate that the size of {beta}-hematin crystal particles and crystallite increases in the presence of chloroquine, suggesting that chloroquine does not impede crystal growth. These findings suggest that chloroquine delays hemozoin production by perturbing the nucleation events of crystals and/or the stability of crystal nuclei. Thus, contrary to prevailing beliefs, this study provides a new perspective on the working mechanism of chloroquine.