Parasite-mediated degradation of synthetic ozonide antimalarials impacts in vitro antimalarial activity

Carlo Giannangelo, Lukas Stingelin, Tuo Yang, Leann Tilley, Susan A. Charman, Darren J. Creek

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite-stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439, and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite-stage parasite cultures exposed to a 3-h drug pulse. This study highlights the impact of increasing parasite load on ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the ozonide antimalarials under conditions of high parasitemia.

Original languageEnglish
Article numbere01566-17
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • Antimalarial activity
  • Artefenomel
  • Arterolane
  • Ozonide
  • Peroxide antimalarial
  • Plasmodium falciparum
  • Stability

Cite this

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abstract = "The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of in vitro drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite-stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439, and this is associated with a reduction in in vitro antimalarial activity. Under conditions of very high parasitemia (90{\%}), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite-stage parasite cultures exposed to a 3-h drug pulse. This study highlights the impact of increasing parasite load on ozonide stability and in vitro antimalarial activity and should be considered when investigating the antimalarial mode of action of the ozonide antimalarials under conditions of high parasitemia.",
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Parasite-mediated degradation of synthetic ozonide antimalarials impacts in vitro antimalarial activity. / Giannangelo, Carlo; Stingelin, Lukas; Yang, Tuo; Tilley, Leann; Charman, Susan A.; Creek, Darren J.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 3, e01566-17, 01.03.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Parasite-mediated degradation of synthetic ozonide antimalarials impacts in vitro antimalarial activity

AU - Giannangelo, Carlo

AU - Stingelin, Lukas

AU - Yang, Tuo

AU - Tilley, Leann

AU - Charman, Susan A.

AU - Creek, Darren J.

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