Identification of an antimalarial synthetic trioxolane drug development candidate

Jonathan L Vennerstrom, Sarah Arbe-Barnes, Reto Brun, Susan A Charman, Francis Chi Keung Chiu, Jacques Chollet, Yuxiang Dong, Arnulf Dorn, Daniel Hunziker, Hugues Matile, Kylie Anne McIntosh, Maniyan Padmanilayam, Josefina Santo Tomas, Christian Scheurer, Bernard Scorneaux, Yuanqing Tang, Heinrich Urwyler, Sergio Wittlin, William Neil Charman

Research output: Contribution to journalArticleResearchpeer-review

521 Citations (Scopus)

Abstract

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which-the sarcoplasmic- endoplasmic reticulum ATPase PfATP6 (ref. 7)-may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.

Original languageEnglish
Pages (from-to)900-904
Number of pages5
JournalNature
Volume430
Issue number7002
DOIs
Publication statusPublished - 19 Aug 2004

Cite this

Vennerstrom, Jonathan L ; Arbe-Barnes, Sarah ; Brun, Reto ; Charman, Susan A ; Chiu, Francis Chi Keung ; Chollet, Jacques ; Dong, Yuxiang ; Dorn, Arnulf ; Hunziker, Daniel ; Matile, Hugues ; McIntosh, Kylie Anne ; Padmanilayam, Maniyan ; Santo Tomas, Josefina ; Scheurer, Christian ; Scorneaux, Bernard ; Tang, Yuanqing ; Urwyler, Heinrich ; Wittlin, Sergio ; Charman, William Neil. / Identification of an antimalarial synthetic trioxolane drug development candidate. In: Nature. 2004 ; Vol. 430, No. 7002. pp. 900-904.
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Vennerstrom, JL, Arbe-Barnes, S, Brun, R, Charman, SA, Chiu, FCK, Chollet, J, Dong, Y, Dorn, A, Hunziker, D, Matile, H, McIntosh, KA, Padmanilayam, M, Santo Tomas, J, Scheurer, C, Scorneaux, B, Tang, Y, Urwyler, H, Wittlin, S & Charman, WN 2004, 'Identification of an antimalarial synthetic trioxolane drug development candidate', Nature, vol. 430, no. 7002, pp. 900-904. https://doi.org/10.1038/nature02779, https://doi.org/10.1038/nature02779

Identification of an antimalarial synthetic trioxolane drug development candidate. / Vennerstrom, Jonathan L; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A; Chiu, Francis Chi Keung; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf; Hunziker, Daniel; Matile, Hugues; McIntosh, Kylie Anne; Padmanilayam, Maniyan; Santo Tomas, Josefina; Scheurer, Christian; Scorneaux, Bernard; Tang, Yuanqing; Urwyler, Heinrich; Wittlin, Sergio; Charman, William Neil.

In: Nature, Vol. 430, No. 7002, 19.08.2004, p. 900-904.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Charman, Susan A

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AU - Chollet, Jacques

AU - Dong, Yuxiang

AU - Dorn, Arnulf

AU - Hunziker, Daniel

AU - Matile, Hugues

AU - McIntosh, Kylie Anne

AU - Padmanilayam, Maniyan

AU - Santo Tomas, Josefina

AU - Scheurer, Christian

AU - Scorneaux, Bernard

AU - Tang, Yuanqing

AU - Urwyler, Heinrich

AU - Wittlin, Sergio

AU - Charman, William Neil

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