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 M). 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 VacuoleChloroquine 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

Hb FP HZ

FP:CQ

CQ

Hb

GluCysGly{ }

NADP

NADPH

GSH

GSSGHMS GR

FP

Fe3+

Fe2+

O2+H+

O2

H2O2

O2+H2O

GSH

GSSG

CQ

GPxReductone

de novosynthesis K+

Na+

Hostcell

Food vacuole

Parasite

1 2

9

10

11

36

8

7

4 5

-

Enzyme

HV

RS

V H

P

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.