Ozonide Antimalarial Activity in the Context of Artemisinin-Resistant Malaria

Research output: Contribution to journalReview ArticleResearchpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)529-543
Number of pages15
JournalTrends in Parasitology
Volume35
Issue number7
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • artemisinin resistance
  • artemisinins
  • mechanism of action
  • ozonide antimalarials

Cite this

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title = "Ozonide Antimalarial Activity in the Context of Artemisinin-Resistant Malaria",
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.",
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Ozonide Antimalarial Activity in the Context of Artemisinin-Resistant Malaria. / Giannangelo, Carlo; Fowkes, Freya J.I.; Simpson, Julie A.; Charman, Susan A.; Creek, Darren J.

In: Trends in Parasitology, Vol. 35, No. 7, 01.07.2019, p. 529-543.

Research output: Contribution to journalReview ArticleResearchpeer-review

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AU - Giannangelo, Carlo

AU - Fowkes, Freya J.I.

AU - Simpson, Julie A.

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AU - Creek, Darren J.

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AB - 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.

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