Artemisinin’s exact biochemical targets are still being fully elucidated, but research has identified several likely protein targets and cellular pathways that are disrupted by the drug’s action. Here’s what is currently known: 

Biochemical Targets of Artemisinin

Once activated by iron (from heme), artemisinin generates free radicals that bind to and alkylate multiple parasite proteins. These are the main biochemical targets:

1. PfATP6 (SERCA-like Calcium ATPase)

• A sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase ortholog in P. falciparum.

• Artemisinin was proposed to inhibit PfATP6, disturbing calcium homeostasis, which is essential for parasite survival and development.

• Note: Some later studies questioned this as the primary target, but it’s still considered important.

2. Parasite Proteins Rich in Iron or Heme Groups

• Hemoglobin-digesting enzymes (like plasmepsins and falcipains) generate heme for artemisinin activation.

• The resulting free radicals alkylate these and other nearby proteins, leading to dysfunction and cell death.

3. Mitochondrial and Redox Pathways

• Artemisinin damages mitochondrial membranes and disrupts electron transport and redox balance.

• This causes oxidative stress, a major mechanism in parasite killing.

4. Proteins Involved in Protein Folding and Translation

• Mass spectrometry has identified artemisinin binding to:

• Translational initiation factors

• Heat shock proteins (e.g., PfHsp70, PfHsp90)

• Ribosomal proteins

• These affect protein synthesis and stress responses.

5. PfKelch13 (Not a Direct Target, But Related to Resistance)

• PfKelch13 is not the target of artemisinin itself, but mutations here (like C580Y) are strongly associated with artemisinin resistance.

• The protein is thought to be involved in endocytosis and ubiquitin pathways, and its mutation slows parasite clearance by blunting damage response.

Summary

Artemisinin doesn’t have one single target—it’s a multi-target drug. Its activated form binds covalently to several critical parasite proteins, especially those in calcium regulation, redox balance, protein folding, and metabolism, leading to rapid parasite death.

References

1. Eckstein-Ludwig, U., Webb, R. J., Van Goethem, I. D., East, J. M., Lee, A. G., Kimura, M., ... & Krishna, S. (2003). Artemisinins target the SERCA of Plasmodium falciparum. Nature, 424(6951), 957–961. https://doi.org/10.1038/nature01813
   
   

2. Meshnick, S. R. (2002). Artemisinin: mechanisms of action, resistance and toxicity. International journal for parasitology, 32(13), 1655-1660.
   
   

3. Wang, J., Zhang, C. J., Chia, W. N., Loh, C. C., Li, Z., Lee, Y. M., ... & Lin, Q. (2015). Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nature communications, 6(1), 10111.
   
   

4. Ismail, H. M., Barton, V., Phanchana, M., Charoensutthivarakul, S., Wong, M. H., Hemingway, J., ... & Ward, S. A. (2016). Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7. Proceedings of the National Academy of Sciences, 113(8), 2080-2085.
   
   

5. Ariey, F., Witkowski, B., Amaratunga, C., Beghain, J., Langlois, A. C., Khim, N., ... & Menard, D. (2014). A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature, 505(7481), 50–55. https://doi.org/10.1038/nature12876

 Unraveling Coronin in Plasmodium falciparum: A Key Player in Artemisinin Resistance?

As resistance to artemisinin-based therapies continues to threaten malaria control efforts, researchers have turned their attention to a suite of genes in Plasmodium falciparum that may play a role in drug tolerance. Among them, coronin is emerging as an intriguing candidate worth watching.

What Is Coronin?

Coronin is a conserved actin-binding protein found in many eukaryotic organisms, including parasites like Plasmodium falciparum. It regulates the parasite’s actin cytoskeleton, impacting critical processes such as:

• Intracellular motility

• Vesicle trafficking

• Host-cell invasion

In P. falciparum, coronin helps maintain the structural integrity and dynamic remodeling of actin filaments—essential for the parasite’s survival and replication.

Coronin, Kelch13 and PI3K in Artemisinin Resistance?

Recent studies have observed mutations in the coronin gene (PF3D7_1251200) in laboratory-evolved artemisinin-resistant parasite lines, although such mutations are not yet widely seen in field isolates (Demas et al., 2018)

Possible Roles in Resistance:

• Altered actin dynamics may affect the stress response pathways under artemisinin exposure.

• Mutations in coronin may act synergistically with other resistance-associated genes, such as Kelch13.

How Does Coronin Compare to Kelch13 and PI3K?

Coronin is part of a larger molecular network possibly involved in resistance. Let’s briefly compare it with two other important players:

Kelch13 (K13): The Primary Genetic Marker

• Gene: PF3D7_1343700

• Role: K13 mutations (e.g., C580Y) are well-established markers for artemisinin resistance.

• Function: Involved in stress response and protein regulation, possibly through protein degradation pathways.

• Use in Surveillance: YES – routinely tracked globally (Mbengue et al., 2015).

PI3K (Phosphoinositide 3-Kinase): A Downstream Effector

• Gene: PF3D7_0515300

• Role: Not directly mutated in resistant parasites but becomes activated downstream of K13 mutations.

• Function: Catalyzes lipid signaling involved in vesicle trafficking and membrane dynamics.

• Connection: Increased PI3K activity and elevated PI3P levels are linked to K13-mediated resistance.

Comparison Table

Feature	Coronin	Kelch13	PI3K (PFPI3K)
Type of Protein	Actin-binding protein	Kelch-domain protein	Lipid kinase
Mutation Status	Observed in lab strains	Mutated in resistant strains	Not mutated (activity changes)
Role in Resistance	Emerging/unclear	Direct marker	Downstream effector
Use in Surveillance	No	Yes	No

Why It Matters

Understanding coronin's contribution to resistance may help refine our models of how artemisinin resistance evolves. Combined with confirmed markers like K13 and downstream players like PI3K, coronin could eventually:

• Serve as a supporting biomarker

• Highlight new targets for therapeutic intervention

• Reveal evolutionary pathways of drug resistance

Conclusion

While coronin is still under investigation, it underscores the complexity of antimalarial resistance and the need to look beyond single-gene models. With molecular tools like CRISPR-Cas9 gene editing, scientists are poised to uncover whether coronin mutations cause, enhance, or compensate for artemisinin resistance.

Bibliography

1. Demas, A. R., Sharma, A. I., Wong, W., Early, A. M., Redmond, S., Bopp, S., Neafsey, D. E., Volkman, S. K., Hartl, D. L., & Wirth, D. F. (2018). Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility. PNAS, 115(50), 12799–12804.
   
   

2. Mbengue, A., Bhattacharjee, S., Pandharkar, T., Liu, H., Estiu, G., Stahelin, R. V., Rizk, S., Njimoh, D. L., Ryan, Y., Chotivanich, K., Nguon, C., Ghorbal, M., Lopez- Rubio, J.-J., Pfrender, M., Emrich, S., Mohandas, N., Dondorp, A. M., Wiest, O., & Haldar, K. (2015). A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature, 520(7549), 683–687. https://doi.org/10.1038/nature14412

3. Batugedara, G., Lu, X. M., Hristov, B., Abel, S., Chahine, Z., Hollin, T., Williams, D., Wang, T., Cort, A., Lenz, T., Thompson, T. A., & Prudhomme, J. (2023). Novel insights into the role of long non-coding RNA in the human malaria parasite, Plasmodium falciparum. Nature Communications, 14, 5086.