Alkylation of proteins by artemisinin

Abstract

Artemisinin and its derivatives are a promising new class of antimalarial agents containing an endoperoxide bridge. [14C]Artemisinin alkylated various proteins in vitro. Between 5 and 18% of added drug bound to hemoproteins such as catalase, cytochrome c, and hemoglobin. However, it did not react with heme-free globin. For catalase and hemoglobin, most of the drug reacted with the protein moiety rather than the heme. Artemisinin bound to human serum albumin (HSA) more efficiently at pH 8.6 than 7.4, more efficiently in Dulbecco's PBS than in Tris-HCl buffer, and better when HSA had been made fatty acid-free. Dihydroartemisinin also bound to HSA, whereas deoxyartemisinin, an inactive derivative, did not. There was no binding between DNA and artemisinin. These data provide insight into the mechanism of the reaction between artemisinin and proteins.

Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells

“…8,12,50–52 For example, depending on the experimental model, some drug derivatives concentrate in the endoplasmic reticulum while others localize in the mitochondrion. 51 It seems a consensus, based on the structure-function relationship of this class of compounds, 52 that artemisinins do not bind specific targets.…”

“…11 These reactive molecules can alkylate thiols and amine moieties of albumin 8 as well as other proteins. 12 However, definitive evidence is lacking to show that this process mediates the activity of artemisinins in non-malarial disease conditions.…”

Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

“…This phenotype is correlated with mutations in the P. falciparum Kelch13 gene [13, 14, 16, 17] and changes in both signalling pathways [18–21] and organellar function [22–29]. Overall, due to the complexity of artemisinin’s mechanism of killing (see citations above and [30–36]), it has been challenging to separate the causes and effects of resistance.…”

Evidence for a Common Non‐Heme Chelatable‐Iron‐Dependent Activation Mechanism for Semisynthetic and Synthetic Endoperoxide Antimalarial Drugs

“…[11] Other researchers have focused on the interactions of artemisinins with specific target proteins. [12][13][14] An early clue to the involvement of iron in the activation mechanism came from studies which showed that the antimalarial activity of artemisinin is strongly antagonized by iron chelators. [15] Since the chelators used in this earlier study are selective for non-heme sources of iron, it is apparent that chelatable parasite iron sources may have an important role to play in the mechanism of action of endoperoxidebased antimalarial drugs.…”