Molecular and Cellular Pharmacology, Vol 5, No 2 (2013)

Artemisinin and Biomolecules: the Continuing Search for Mechanism of Action

Abstract

This review was conceived with the aim of presenting a comprehensive account of the molecular interactions of artemisinin class of antimalarials and delineating it in the context of the different theoretical models of artemisinin mechanism of action. As the most rapidly acting schizontocide, artemisinin with its derivatives are in the forefront of the battle against malaria parasite. Forty one years after its extraction, the exact mechanism of action of artemisinin and its derivatives has not been unequivocally elucidated. Understanding its exact mode of action could help in new drug discovery that would circumvent the resistance mechanism of P. falciparum, present the additional and simpler tool of detecting and monitoring the spread of these resistant mutants by providing a surrogate marker of artemisinin resistance and, perhaps aid in the elimination of this menace. Artemisinin actions have been linked to the generation of radicals, which damage parasite vital biomolecules by alkylation, and oxidative stress in the microenvironment of its activation. Interference with the parasite heme-detoxification pathways, abolition of parasite mitochondrial inner membrane electropotential, inhibition of PfATP6 and apoptosis induction have all been documented as mediating artemisinin effects. At present, inhibition of PfATP6 as mediating artemisinin effects appears to attract the most attention. However, the picture is incomplete and sight should not be lost of equally strong and compelling facts implicating other molecular targets and the biochemical basis of the well demonstrated phenomenon of quiescence of ring forms under artemisinin pressure.

Keywords: Artemisinin; Antimalarials; PfATP6; Heme detoxification; Oxidative stress; Radical formation; Plasmodium falciparum.

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