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Malaria treatment
(References: PubMed, Google, Ginsburg H
and Golenser J publications)
CHING-HAO (Artemisinin) is isolated from
Artemisia annua and used in chinese medicine
Trophozoite- EM
Labile iron in P.falciparum infected erythrocytes induce fragmentation of DNA
-Fe2+
+ H2O2 ----> Fe3+ + .OH + OH
Ridley RG, Nature. 2003, 424 (6951): 887-9
Artemisinin inhibits plasmodia by two mechanisms:
1. Production of free radicals which affects different
macromolecules.
2. Specific interference with PfATP6 (Ca-2+ATPase
(SERCA)). This interference is also mediated by iron
induced damage.
Thapsigargin is an inhibitor of SERCA, has structural
similarity to artemisinin, lacks peroxide bridge and
interferes with the anti-plasmodial activity of artemisinin.
Iron chelator (Desferal) abrogates artemisinin effect on
SERCA.
The first mechanism explains the non-specific effect on various
eukaryotic cells (ED50 mM). The second one explains the
specificity towards Plasmodium falciparum (ED50 nM).
Spread of chloroquine resistance
The Mechanism of Accumulation of Chloroquine in the Parasite Food Vacuole
Chloroquine travels down a pH gradient and inside the parasite becomes diprotonated.
This form of the drug (shown in blue) is impermeable to biological membranes.On the
right of the figure is a generic structure of a parasite targeted artemisinin derivative
Food vacuole
Hb
1
2
{ }
HM
S
K+
11
FP
6
3
GSS
G
O-2+H+
Fe3+
Fe2+
Parasite
FP:CQ
GSH
Reductone
HZ
CQ
9
de novo 8
synthesis
NADP
7
G
R
NADPH
FP
Hb
Glu
Cys
Gly
Host
cell
4
O2
10
CQ
Enzyme
H2O2
GSH
GPx 5
O2+H2O
GSSG
Na+
V
H
P
V
S
R
H
Table 1. Reported polymorphisms on the Plasmodium
falciparum chloroquine resistance transporter gene,
pfcrt, on chromosome 7.
Wernsdorfer, Curr Opin Infect Dis, 2003, 16, 553-558.