title: 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 combinations with existing antimalarials, we demonstrated that harmine potentiates the effect of chloroquine and artemisinin in vitro and in the Plasmodium berghei mouse model. These findings have implications for the development of novel therapeutic combinations that are synergistic with existing antimalarials.
authors.affiliation: Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dea
authors.initials: D
authors.lastname: Shahinas
authors.forename: Gregory
authors.initials: G
authors.lastname: Macmullin
authors.forename: Christan
authors.initials: C
authors.lastname: Benedict
authors.forename: Ian
authors.initials: I
authors.lastname: Crandall
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Pillai
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006246:Harmaline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006247:Harmine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D018841:HSP90 Heat-Shock Proteins; C007904:harmalol; D006247:Harmine; D002738:Chloroquine; C031327:artemisinin; D006246:Harmaline