Harmine is a potent antimalarial targeting Hsp90 and synergizes with chloroquine and artemisinin.

ABSTRACT: Previous studies have shown an antimalarial effect of total alkaloids extracted from leaves of Guiera senegalensis from Mali in West Africa. We independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibited Plasmodium falciparum heat shock protein 90 (PfHsp90) ATP-binding domain. In this study, we confirmed harmine-PfHsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [K(d)] of 40 μM). In contrast, the related compound harmalol bound human Hsp90 (HsHsp90) (K(d) of 224 μM) more tightly than PfHsp90 (K(d) of 7,010 μM). Site-directed mutagenesis revealed that Arg98 in PfHsp90 is essential for harmine selectivity. In keeping with our model indicating that Hsp90 inhibition affords synergistic combinati

SUBMITTER: Shahinas D 

PROVIDER: S-EPMC3421604 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature