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 language | English |
|---|---|
| Article number | e01566-17 |
| Number of pages | 14 |
| Journal | Antimicrobial Agents and Chemotherapy |
| Volume | 62 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Mar 2018 |
Keywords
- Antimalarial activity
- Artefenomel
- Arterolane
- Ozonide
- Peroxide antimalarial
- Plasmodium falciparum
- Stability
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
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.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - Antimalarial activity
KW - Artefenomel
KW - Arterolane
KW - Ozonide
KW - Peroxide antimalarial
KW - Plasmodium falciparum
KW - Stability
UR - http://www.scopus.com/inward/record.url?scp=85042377247&partnerID=8YFLogxK
U2 - 10.1128/AAC.01566-17
DO - 10.1128/AAC.01566-17
M3 - Article
VL - 62
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 1098-6596
IS - 3
M1 - e01566-17
ER -