Artemisinin and its derivatives

Artemisinin was first isolated in 1971 by Tu Youyou from the plant Artemisia annua, a herb that has commonly been used in Chinese traditional medicine [28]. Due to the great positive impact of artemisinin in combating malaria, Youyou was awarded the joint Nobel Prize in Physiology or Medicine in 2015 for “her discoveries concerning a novel therapy against malaria” [29]. Artemisinin has been shown to be efficacious against all multi-drug resistant forms of P. falciparum. The most common derivatives of artemisinin are artemether, artesunate and arteether. These semi-synthetic derivatives are prodrugs which are transformed to the active metabolite, dihydroartemisinin. The use of artemisinins has been integral in the fight against malaria with ACT making up the majority of modern-day treatments [30]. Although slow to develop, the first report of resistance to artemisinin was in western Cambodia in 2008 [31]. Ten years later, in February of 2018, a report was published identifying more than 30 independent cases of artemisinin resistance in southeast Asia, specifically with resistance to the dihydroartemisinin-piperaquine combination therapy [32].

The mechanism of action (MoA) through which artemisinin acts has been widely debated [33]. The most accepted theory is that the molecule is activated by haem to generate free radicals, which in turn damage proteins required for parasite survival [34, 35]. Still, evidence for a number of other possible mechanisms have been found. In 2013, a computational approach was taken to determine the MoA based around previous studies which identified haem and Pf ATP6 (Ca²⁺ transporter) as potential MoAs [36]. More recently in 2015, artemisinin was shown to be associated with the up-regulation of the unfolded protein response (UPR) pathways which may be linked to decreased parasite development [37]. Another study showed that artemisinin was is a potent inhibitor of P. falciparum phosphatidylinositol-3-kinase (Pf PI3K) [38].