Stage-specific pharmacodynamic chloroquine and pyronaridine action on artemisinin ring-stage resistant Kelch C580Y mutation Plasmodium falciparum correlates to hemozoin inhibition process
Year: 2024
Type: article
Abstract: ABSTRACT The antimalarial quinolines pyronaridine and chloroquine both inhibit hemozoin crystallization, predominately produced by Plasmodium falciparum intra-erythrocytic trophozoite stage parasites. Pyronaridine extends activity to ring-stage chloroquine-sensitive parasites, in contrast to chloroquine. Here, we investigated chloroquine and pyronaridine hemozoin inhibition type correlated to stage-specific activity on chloroquine-resistant ring-stage artemisinin sensitive and resistant P. falciparum CamWT and CamWT-C580Y parasites. Pyronaridine (2.8 μM) is tenfold more potent at beta-hematin nucleation than chloroquine (40 μM). Both pyronaridine and chloroquine (0.2 and 0.7 μM, respectively) had similar sub-μM inhibition of beta-hematin extension. P. falciparum CamWT-C580Y parasites produce smaller width hemozoin crystals which extend less than isogenic CamWT hemozoin. Stage-specific pulse dose pyronaridine and chloroquine on CamWT-C580Y or CamWT isogenic parasites observed 3- to 4-fold higher pyronaridine IC 50 s compared to 10- to 15-fold higher chloroquine on most CamWT-C580Y to CamWT stages. These findings collectively show that hemozoin nucleation inhibition widens stage-specific pyronaridine activity on P. falciparum drug-resistant parasites.
DOI: 10.1128/aac.01208-24
Authors: Abeer Sayeed, Revie Atkinson, Peter G. Vekilov, Jeffrey D. Rimer, David J. Sullivan
Institutions: Johns Hopkins University, University of Houston
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G3916139033, G4211978696
OpenAlex ID: W4405323318