In Vitro Investigation Unveiling New Insights into the Antimalarial Mechanism of Chloroquine: Role in Perturbing Nucleation Events during Heme to β-Hematin Transformation.

Rahul Singh, Rashmi Singh, Velaga Srihari, Ravindra D Makde

ACS infectious diseases 2023 Aug 11

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Malaria parasites generate toxic heme during hemoglobin digestion, which is neutralized by crystallizing into inert hemozoin (β-hematin). Chloroquine blocks this detoxification process, resulting in heme-mediated toxicity in malaria parasites. However, the exact mechanism of chloroquine's action remains unknown. This study investigates the impact of chloroquine on the transformation of heme into β-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 β-hematin formation. Scanning electron microscopy (SEM) and X-ray powder diffraction (XRD) studies indicate that the size of β-hematin crystal particles and crystallites 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.

Citation

Rahul Singh, Rashmi Singh, Velaga Srihari, Ravindra D Makde. In Vitro Investigation Unveiling New Insights into the Antimalarial Mechanism of Chloroquine: Role in Perturbing Nucleation Events during Heme to β-Hematin Transformation. ACS infectious diseases. 2023 Aug 11;9(8):1647-1657