Ozonide Antimalarial Activity in the Context of Artemisinin-Resistant Malaria

Carlo Giannangelo; Freya J I Fowkes; Julie A Simpson; Susan A Charman; Darren J Creek

doi:10.1016/j.pt.2019.05.002

Ozonide Antimalarial Activity in the Context of Artemisinin-Resistant Malaria

Trends Parasitol. 2019 Jul;35(7):529-543. doi: 10.1016/j.pt.2019.05.002. Epub 2019 Jun 5.

Authors

Carlo Giannangelo¹, Freya J I Fowkes², Julie A Simpson³, Susan A Charman⁴, Darren J Creek⁵

Affiliations

¹ Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia.
² Burnet Institute, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Victoria, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Victoria, Australia.
³ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Victoria, Australia.
⁴ Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia.
⁵ Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia. Electronic address: darren.creek@monash.edu.

PMID: 31176584
DOI: 10.1016/j.pt.2019.05.002

Abstract

The ozonides are one of the most advanced drug classes in the antimalarial development pipeline and were designed to improve on limitations associated with current front-line artemisinin-based therapies. Like the artemisinins, the pharmacophoric peroxide bond of ozonides is essential for activity, and it appears that these antimalarials share a similar mode of action, raising the possibility of cross-resistance. Resistance to artemisinins is associated with Plasmodium falciparum mutations that allow resistant parasites to escape short-term artemisinin-mediated damage (elimination half-life ~1 h). Importantly, some ozonides (e.g., OZ439) have a sustained in vivo drug exposure profile, providing a major pharmacokinetic advantage over the artemisinin derivatives. Here, we describe recent progress made towards understanding ozonide antimalarial activity and discuss ozonide utility within the context of artemisinin resistance.

Keywords: artemisinin resistance; artemisinins; mechanism of action; ozonide antimalarials.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Artemisinins / pharmacology*
Drug Resistance / drug effects*
Drug Resistance / genetics
Heterocyclic Compounds / pharmacology*
Heterocyclic Compounds / therapeutic use*
Humans
Malaria / drug therapy*
Plasmodium falciparum / drug effects*
Plasmodium falciparum / genetics

Substances

1,2,4-trioxane
Artemisinins
Heterocyclic Compounds