Artemisinin-Based Antimalarial Drug Development

Artemisinin and its semisynthetic derivatives have underpinned global malaria control for over two decades. Derived from the sweet wormwood plant, these endoperoxide compounds exhibit rapid parasite clearance by generating reactive intermediates that alkylate multiple targets within the Plasmodium parasite. The advent of artemisinin combination therapies (ACTs), pairing fast-acting artemisinin derivatives with longer-lasting partner drugs, has boosted treatment efficacy and helped delay the evolution of resistance. However, the emergence of Kelch13 (K13) mutations in Plasmodium falciparum has compromised parasite clearance rates across Southeast Asia and threatens to erode these gains. In response, medicinal chemists have engineered novel endoperoxides and tetraoxanes with enhanced pharmacokinetic profiles, single-dose cure potential and no cross-resistance to prevalent K13 variants. Parallel advances in chemical proteomics and genome editing have deepened insights into drug activation pathways, parasite stress responses and the biochemical networks perturbed by artemisinin and its successors. Together, these developments chart a path towards next-generation therapies capable of sustaining antimalarial efficacy in the face of evolving resistance.

Research from Nature Portfolio

Recent studies have employed unbiased chemical proteomics to map the extensive repertoire of parasite proteins alkylated by artemisinin. One investigation using an alkyne-tagged probe revealed over one hundred covalent targets spanning haemoglobin digestion, glycolysis and antioxidant defence pathways, and demonstrated that haem derived from the parasite’s own biosynthesis acts as the principal activator of the endoperoxide bond. In parallel, a multinational drug-discovery programme has delivered a synthetic tetraoxane molecule that retains potent nanomolar activity against both K13 wild-type and C580Y mutant parasites. This candidate exhibits favourable pharmacokinetics compatible with single-dose regimens and shows no cross-resistance with the most widespread resistance-conferring mutation, representing a significant advance toward a durable artemisinin successor.

Artemisinin-Based Antimalarial Drug Development publication trend

The graph below shows the total number of articles in artemisinin-based antimalarial drug development across all publications each year (not limited to Nature Index journals).

Technical terms

Endoperoxide: A chemical structure containing a peroxide bridge essential for artemisinin activation.

Artemisinin combination therapies (ACTs): Regimens pairing artemisinin derivatives with partner drugs to enhance efficacy and delay resistance.

K13 mutations: Genetic changes in the Kelch13 protein associated with artemisinin resistance in Plasmodium falciparum.

Ozonides: Synthetic endoperoxide antimalarials designed to mimic artemisinin’s mechanism with altered pharmacokinetics.

Proteomics: Large-scale study of proteins and their interactions within a biological system.

Photoaffinity probe: A molecule incorporating a light-activated tag to identify drug–protein interactions.

References

1. Photoaffinity probe‐based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum. iMeta (2024).
2. Plasmodium falciparum K13 Mutations Differentially Impact Ozonide Susceptibility and Parasite Fitness In Vitro. mBio (2017).
3. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nature Communications (2015).
4. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nature Communications (2017).
5. Comparison of the Exposure Time Dependence of the Activities of Synthetic Ozonide Antimalarials and Dihydroartemisinin against K13 Wild-Type and Mutant Plasmodium falciparum Strains. Antimicrobial Agents and Chemotherapy (2016).