Neglected Diseases - Drug Design and Discovery - page 349

FIGURE 21.9 Two orthogonal views of a suggested binding mode of chloroquine (green) to hemozoin
(yellow). Hetero-atoms are colored red, blue, and orange for oxygen, nitrogen, and iron, respectively. (Figure
prepared by Dr. F. S. Jørgensen, University of Copenhagen, Denmark.)
The complexation between chloroquine and hemozoin further contributes to the concentration
of choroquine in the food vacuole. Actually, the concentration of chloroquine, in sensitive parasites,
is four orders of magnitude higher inside the vacuole than outside. The presented model also con-
i rms the i nding that variations in the side chain, only to a minor extent, inl uence the strength of
the association. Notice the absence of stereocenters in the porphyrin nucleus. The achirality of this
target explains that the two enantiomers of chloroquine have the same binding afi nity. In agreement
with the target being heme, chloroquine affects the erythrocytic stages of the parasite only, the only
stages in which hemozoin is formed.
21.5.2 D RUGS T ARGETING A Ca 2+ P UMP OF P LASMODIUM P ARASITES
Whereas European physicians did not get access to an efi cient antimalarial drug until the sixteenth
century, Chinese authors described the effect of qing hao and cao hao against intermittent fever
two thousand years ago. Since the Chinese way of describing symptoms of diseases is very different
from the Western terminology, intermittent fever cannot in a simple way be translated into a well-
known term. However, intermittent fever could include the fever caused by malaria. Quing hao has
later been identii ed as Artemisia apiacea (Asteraceae) and cao hao as A. annua (sweet wormwood).
In the 1970s, Chinese scientists isolated artemisinin ( 21.8 ) (Figure 21.10) from both these species
and showed that the compound was a potent antimalarial agent. Artemisinin is an irregular sesquit-
erpene lactone containing an endoperoxide bridge. Synthetic analogs, in which the peroxide bridge
has been removed, show no activity toward Plasmodium parasites. The amount of artemisinin that
may be extracted from the wormwood varies between 0.01% and 0.8% of dry weight, a serious limi-
tation for the commercialization of the drug.
Originally, it was suggested that artemisinin by reaction with the iron (II) ion of heme gener-
ates a radical, which reacted with the heme skeleton and thereby prevented this from precipita-
tion (Scheme 21.1). Although this idea still is favored in some laboratories, later studies indicate
that artemisinin inhibits a plasmodial intracellular calcium pump ( Pf ATP6). All cells maintain
a low cytosolic Ca 2+ concentration by removing Ca 2+ from the cytosol with a pump sitting in the
membrane of the endoplasmic reticulum. Blocking this pump yields a high cytosolic Ca 2+ con-
centration, which eventually leads to cell death (Figure 21.6). A crucial difference between the
mammalian pump, the sarco-/endoplasmic calcium ATPase (SERCA), and the Pf ATP6 pump is the
presence of Glu255 in SERCA, whereas a Leu is located in the equivalent position 263 in Pf ATP6.