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Chemical proteomics approach reveals the direct targets and the heme-dependent
activation mechanism of artemisinin in Plasmodium falciparum using an
artemisinin-based activity probe
#MMPMID28357359
Wang J
; Lin Q
Microb Cell
2016[Apr]; 3
(5
): 230-231
PMID28357359
show ga
Artemisinin and its analogues are currently the most effective anti-malarial
drugs. The activation of artemisinin requires the cleavage of the endoperoxide
bridge in the presence of iron sources. Once activated, artemisinins attack
macromolecules through alkylation and propagate a series of damages, leading to
parasite death. Even though several parasite proteins have been reported as
artemisinin targets, the exact mechanism of action (MOA) of artemisinin is still
controversial and its high potency and specificity against the malaria parasite
could not be fully accounted for. Recently, we have developed an unbiased
chemical proteomics approach to directly probe the MOA of artemisinin in P.
falciparum. We synthesized an artemisinin analogue with an alkyne tag, which can
be coupled with biotin through click chemistry. This enabled selective
purification and identification of 124 protein targets of artemisinin. Many of
these targets are critical for the parasite survival. In vitro assays confirmed
the specific artemisinin binding and inhibition of selected targets. We thus
postulated that artemisinin kills the parasite through disrupting its biochemical
landscape. In addition, we showed that artemisinin activation requires heme,
rather than free ferrous iron, by monitoring the extent of protein binding using
a fluorescent dye coupled with the alkyne-tagged artemisinin. The extremely high
level of heme released from the hemoglobin digestion by the parasite makes
artemisinin exceptionally potent against late-stage parasites (trophozoite and
schizont stages) compared to parasites at early ring stage, which have low level
of heme, mainly derived from endogenous synthesis. Such a unique activation
mechanism also confers artemisinin with extremely high specificity against the
parasites, while the healthy red blood cells are unaffected. Our results provide
a sound explanation of the MOA of artemisinin and its specificity against malaria
parasites, which may benefit the optimization of treatment strategies and the
battle against the emerging drug resistance.
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