Kelch-like protein K13 (PfK13) (PfK13)

The Plasmodium falciparum artemisinin combination target system refers to the collective molecular targets and pathways addressed by Artemisinin-based Combination Therapies (ACTs), the frontline treatment for malaria (WHO, 2023). The central molecular component of this system is the Kelch 13 (PfK13) protein, which serves as the primary marker for artemisinin resistance and plays a crucial role in hemoglobin endocytosis and the parasite's proteostatic stress response (PubMed, 2016; PMC, 2020). Artemisinin and its derivatives are prodrugs that, upon activation by parasite-derived heme, generate reactive carbon-centered radicals that promiscuously alkylate and inhibit numerous parasite proteins, including the sarco/endoplasmic reticulum Ca2+-ATPase (PfATP6) and phosphatidylinositol-3-kinase (PfPI3K) (Nature, 2003; PMC, 2015). The combination aspect of the system involves partner drugs such as lumefantrine, piperaquine, or mefloquine, which possess longer half-lives and distinct mechanisms of action, such as the inhibition of heme detoxification into non-toxic hemozoin (Antimicrob Agents Chemother, 2021). This dual-action approach is essential for ensuring the complete clearance of parasites and mitigating the development of resistance (WHO, 2023). Mutations in the PfK13 propeller domain are the hallmark of artemisinin resistance, leading to reduced hemoglobin uptake and decreased drug activation in the early ring stage of the parasite's life cycle (Malaria World, 2024). Understanding this target system is critical for monitoring drug efficacy and developing next-generation antimalarials to combat spreading resistance in endemic regions (Expert Rev Anti Infect Ther, 2016).

Other names

Kelch-like protein K13PF3D7_1343700Artemisinin resistance proteinKelch 13Plasmodium falciparum Kelch 13

Artemisinin derivatives are activated by heme to form reactive radicals that covalently alkylate multiple parasite proteins, including PfATP6 and PfPI3K, disrupting essential cellular processes (Nature, 2003; PMC, 2015). Partner drugs in ACTs, such as lumefantrine and piperaquine, inhibit the detoxification of heme into hemozoin (Antimicrob Agents Chemother, 2021). Mutations in PfK13 mediate resistance by reducing hemoglobin endocytosis and artemisinin activation (Malaria World, 2024).