Mechanism of antimalarial action of the synthetic trioxolane RBX11160 (OZ277).

Abstract:

: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.

authors

Uhlemann AC,Wittlin S,Matile H,Bustamante LY,Krishna S

doi

10.1128/AAC.01064-06

subject

Has Abstract

pub_date

2007-02-01 00:00:00

pages

667-72

issue

2

eissn

0066-4804

issn

1098-6596

pii

AAC.01064-06

journal_volume

51

pub_type

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