The recent advances of chemical biology in artemisinin target and mechanism

Abstract

Artemisinin is a natural compound that is extracted from the plant Artemisia annua. While it was used to treat fever and pain in the past, it is currently approved by World Health Organization (WHO) to be used in combating malaria. It is an effective anti-malarial drug because of its high efficacy even towards multi-drug resistant Plasmodium strains and exhibits no significant side effects in humans. However, artemisinin has poor solubility in water or oil, poor bioavailability and a short half-life in vivo . Therefore, derivatives of artemisinin consisting of semi-synthetic and fully synthetic compounds with improved properties have been synthesized. Semi-synthetic derivatives include artesunate, artemether and dihydroartemisinin. Artemisinin and its derivatives are sesquiterpene lactones that contain a unique endoperoxide bond in its trioxane ring, which is essential for their anti-malarial activity. The importance of this bond is shown by the findings of studies that the abrogation of the endoperoxide bond led to a significant reduction in toxicity of the drugs. For example, the removal of one O-atom in the endoperoxide moiety was associated with a complete loss of anti-malarial activity. The activation mechanism of artemisinin is hypothesized to involve the reduction of the endoperoxide bond by Fe2+, which is a catalyst that can generate free radicals from peroxidic structures. The selective toxicity of the drug towards parasite-infected cells as compared to non-infected cells is attributed to the higher heme level in parasite-infected cells. In malarial parasite-infected red blood cells, the parasites break down hemoglobin in the food vacuole to gain amino acids for synthesis of their parasite-specific proteins. As a result, heme is released, which can be further degraded into iron in the vacuole. Therefore, hemoglobin degradation gives rise in an increase in both heme and free iron level in infected erythrocytes. As a result, whether heme or iron is the crucial activator of the drug is yet to be elucidated. One of the pleiotropic effects of the drug is that the reduced endoperoxide bond forms cytotoxic carbon-centered radicals that can alkylate target proteins and affect their functions. Other effects include the alkylation of heme, generation of reactive oxygen species (ROS) and inhibition of PfATP6, which is the P. falciparum ortholog of the endoplasmic reticulum Ca2+ pump. Some studies have also found that artemisinin builds up within neutral lipids and damage the parasite membrane. The combination of these toxic effects of artemisinin and its derivatives result in parasitic death. Artemisinin is used to relieve pain and fever in the older days. Today, artemisinin is widely used as an anti-malarial drug as our first line of defense to combat the emergence of drug resistance malaria parasite. Besides its anti-malarial properties, artemisinin is being investigated in other diseases. It is found to possess a wide spectrum of pharmacological activities, including anticancer, anti-asthma etc. However, its mechanism of action (MOA) is still not fully understood. Recently, “omics” approach has been used in identify the targets and unravel the mechanism of action of artemisinin. This review will summarize the recent progress in artemisinin target and mechanism study.