Mechanism of antimalarial action of the synthetic trioxolane RBX11160 (OZ277).
RBX11160 (OZ277) is a fully synthetic peroxidic antimalarial in clinical development. To study the possible mechanisms of action of RBX11160, we have examined its ability to inhibit PfATP6, a sarcoplasmic reticulum calcium ATPase and proposed target for semisynthetic peroxidic artemisinin derivatives. RBX11160 inhibits PfATP6 (apparent half-maximal inhibitory constant=7,700 nM) less potently than artemisinin (79 nM). Inhibition of PfATP6 is abrogated by desferrioxamine, an iron-chelating agent. Consistent with this finding, the killing of Plasmodium falciparum organisms by RBX11160 in vitro is antagonized by desferrioxamine. Artesunate and RBX11160 also act antagonistically against P. falciparum in vitro. A fluorescent derivative of RBX11160 localizes to the parasite cytosol in some parasites and to the food vacuole in other parasites. These data demonstrate that there are both similarities and differences between the antimalarial properties of RBX11160 and those of semisynthetic antimalarials such as artesunate and artemisinin.
Uhlemann
Anne-Catrin
AC
Division of Cellular and Molecular Medicine, Centre for Infection, St. George's University of London, and Dept. of Infectious Diseases, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, United Kingdom.
Wittlin
Sergio
S
Matile
Hugues
H
Bustamante
Leyla Y
LY
Krishna
Sanjeev
S
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology; D000077332:Artesunate; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000188:drug therapy; D018613:Microscopy, Confocal; D010545:Peroxides / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000648:ultrastructure; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology
C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D037621:Artemisinins; D006573:Heterocyclic Compounds, 1-Ring; D010545:Peroxides; D012717:Sesquiterpenes; D013141:Spiro Compounds; C489136:arterolane; D000077332:Artesunate; C031327:artemisinin; D000252:Calcium-Transporting ATPases