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Review
. 2024 Sep 20;9(9):223.
doi: 10.3390/tropicalmed9090223.

Antimalarial Mechanisms and Resistance Status of Artemisinin and Its Derivatives

Dan Zheng  1   2 , Tingting Liu  1 , Shasha Yu  1 , Zhilong Liu  1 , Jing Wang  1 , Ying Wang  1   2
Affiliations
Review

Antimalarial Mechanisms and Resistance Status of Artemisinin and Its Derivatives

Dan Zheng et al. Trop Med Infect Dis. .

Abstract

Artemisinin is an endoperoxide sesquiterpene lactone isolated from Artemisia annua and is often used to treat malaria. Artemisinin's peroxide bridge is the key structure behind its antimalarial action. Scientists have created dihydroartemisinin, artemether, artesunate, and other derivatives preserving artemisinin's peroxide bridge to increase its clinical utility value. Artemisinin compounds exhibit excellent efficacy, quick action, and minimal toxicity in malaria treatment and have greatly contributed to malaria control. With the wide and unreasonable application of artemisinin-based medicines, malaria parasites have developed artemisinin resistance, making malaria prevention and control increasingly challenging. Artemisinin-resistant Plasmodium strains have been found in many countries and regions. The mechanisms of antimalarials and artemisinin resistance are not well understood, making malaria prevention and control a serious challenge. Understanding the antimalarial and resistance mechanisms of artemisinin drugs helps develop novel antimalarials and guides the rational application of antimalarials to avoid the spread of resistance, which is conducive to malaria control and elimination efforts. This review will discuss the antimalarial mechanisms and resistance status of artemisinin and its derivatives, which will provide a reference for avoiding drug resistance and the research and development of new antimalarial drugs.

Keywords: Plasmodium; artemisinin; kelch13; malaria; mechanism of action; resistance.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structures of artemisinin and its derivatives.
Figure 2
Figure 2
The antimalarial mechanism of artemisinin. Heme and iron produced by hemozoin can activate artemisinin to produce free radicals. The activated artemisinin disrupts the physiological functions of Plasmodium by targeting proteins, lipids, and nucleic acids, leading to the parasites’ death. The asterisk signifies the activated form of ART. Abbreviations: Art, artemisinin.
Figure 3
Figure 3
The mechanism of artemisinin resistance. The PfK13 mutation causes the reduced endocytosis of host hemoglobin, resulting in lowered levels of hemoglobin catabolism and the reduced activation of artemisinin drugs. The K13 mutation also leads to increased resistance to artemisinin by reducing the damage of proteins and enhancing the repair of DNA damage. In addition, Pfcoronin, AP-2μ, and UBP1 mutations may block artemisinin activation, resulting in a reduced killing effect of artemisinin. Abbreviations: ART, artemisinin; Hb, hemoglobin; Pfcoronin, Plasmodium falciparum actin-binding protein coronin; AP-2μ: adaptor protein 2μ; UBP1, upstream binding protein 1.
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