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 Fe 2+ + H 2 O > Fe 3+ +.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 (ED 50  M). The second one explains the specificity towards Plasmodium falciparum (ED 50 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

Hb FP HZ FP : CQ CQ Hb Glu Cys Gly {} NADP NADPH GSH GSS G HM S GRGR FP Fe 3+ Fe 2+ O 2 +H + O 2 H 2 O 2 O 2 +H 2 O GSH GSSG CQ GPx Reductone de novo synthesis K+K+ Na + Host cell Food vacuole Parasite Enzyme

H V RS VH P

Table 1. Reported polymorphisms on the Plasmodium falciparum chloroquine resistance transporter gene, pfcrt, on chromosome 7. Wernsdorfer, Curr Opin Infect Dis, 2003, 16,