Anti-malarial ozonides OZ439 and OZ609 tested at clinically relevant compound exposure parameters in a novel ring-stage survival assay

Abstract Background Drug efficacy against kelch 13 mutant malaria parasites can be determined in vitro with the ring-stage survival assay (RSA). The conventional assay protocol reflects the exposure profile of dihydroartemisinin. Methods Taking into account that other anti-malarial peroxides, such a...

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Bibliographic Details
Published in:Malaria Journal
Main Authors: Annabelle Walz, Didier Leroy, Nicole Andenmatten, Pascal Mäser, Sergio Wittlin
Format: Article in Journal/Newspaper
Language:English
Published: BMC 2019
Subjects:
Malaria
RSA
Plasmodium falciparum
kelch 13
Cam3.IR539T
Artemisinins
Arctic medicine. Tropical medicine
RC955-962
Infectious and parasitic diseases
RC109-216
Arctic
Online Access:https://doi.org/10.1186/s12936-019-3056-8
https://doaj.org/article/4a4c425c4414479485ec6851ec4d9c8a
Description
Summary:Abstract Background Drug efficacy against kelch 13 mutant malaria parasites can be determined in vitro with the ring-stage survival assay (RSA). The conventional assay protocol reflects the exposure profile of dihydroartemisinin. Methods Taking into account that other anti-malarial peroxides, such as the synthetic ozonides OZ439 (artefenomel) and OZ609, have different pharmacokinetics, the RSA was adjusted to the concentration–time profile of these ozonides in humans and a novel, semi-automated readout was introduced. Results When tested at clinically relevant parameters, it was shown that OZ439 and OZ609 are active against the Plasmodium falciparum clinical isolate Cam3.IR539T. Conclusion If the in vitro RSA does indeed predict the potency of compounds against parasites with increased tolerance to artemisinin and its derivatives, then the herein presented data suggest that following drug-pulses of at least 48 h, OZ439 and OZ609 will be highly potent against kelch 13 mutant isolates, such as P. falciparum Cam3.IR539T.

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