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Malaria, iron and antimalarial drugs - new research brings us one step closer
Dr Timothy J Egan, Department of Chemistry,
University of Cape Town
 Malaria is one of the most significant infectious diseases in the world. It
is endemic through the entire tropical region of the Earth, except for high
mountain areas, deserts and a few islands. Nonetheless, the problem is by far
the most significant in Africa, where it accounts for about 90% of infections and
deaths. Exact figures for the number of infections and deaths are not available,
but it is generally considered that about one third of the Earth's population is
at risk, and that there are 100 - 200 million infections and 1 - 3 million
deaths annually. Most of the deaths occur in children under the age of five
years. Malaria is the fifth largest killer out of all the infectious diseases
world-wide, and is a leading killer in Africa. It places a huge burden on the
continent's economy and social fabric.
There are several reasons why malaria is such a serious problem in Africa.
Firstly, a species of mosquito called Anopheles gambiae, which exists only in
Africa, specialises in feeding exclusively on humans. This mosquito lives inside
people's houses and is thus very efficient at transmitting malaria from infected
individuals to uninfected people. The presence of this mosquito in Africa is
probably a result of mankind's origin on this continent. A second factor is the
very high incidence of malaria in Africa, which makes it more difficult to
control than in areas where the incidence is lower. This already difficult
situation has been made worse by three additional factors. Poverty and civil
wars have weakened malaria control measures, changes in agricultural practices
(such as introduction of irrigation) have brought people into closer contact with
mosquitoes and finally population movements have caused an influx of infected
individuals into areas where malaria may previously have been less prevalent.
There are concerns that climate change may also worsen the problem. Superimposed
on all of these is the occurrence of drug resistant malaria, especially
chloroquine resistant malaria. This makes it far more difficult to reduce
malaria infection in the population, further increasing its incidence.
The disease is caused by four species of single-celled parasites of the genus
Plasmodium. Most infections are caused by Plasmodium falciparum and
Plasmodium
vivax. Deaths are caused almost exclusively by the former, while the latter
causes a form of malaria that is recurrent in the infected patient (causing
bouts of disease long after the original infection). These parasites have a
complicated life cycle, being transmitted from one individual to the next by
mosquitoes. The life cycle thus consists of a mosquito stage, where it develops
inside the mosquito. It also has two main stages in the human, first in the
liver and then in the blood. The liver stage, which has no symptoms, lasts for
about a week to ten days after the bite of the infected mosquito. Thereafter the
parasites emerge into the blood, with the onset of symptoms. Malaria treatment
is therefore directed at the blood stage.
Blood stage malaria parasites live inside human red blood cells. This helps
them to conceal themselves from the immune system and is one of the reasons why
the development of a vaccine has been so elusive. Nonetheless, a red blood cell
is a harsh environment. Almost the only source of nourishment available inside
the red cell is haemoglobin, a protein responsible for transporting oxygen in
humans and other vertebrates. This protein has attached to it an iron containing
substance called haem. It is actually this iron that bonds to oxygen. The
parasite uses the protein part of haemoglobin as food, but haem is a waste
product from its point of view and it is faced with the problem of ridding
itself of this haem.
For almost a century it has been known that at least a part
of the haem is incorporated into an insoluble crystalline substance called
malaria pigment. This pigment acts as a sink for removal of haem because it is
very insoluble. However, until now it was not known whether all of the haem was
removed in this way, or whether other, possibly dominant pathways exist for its
removal.
This question is of considerable importance. There is accumulating evidence
produced over the last decade that certain antimalarial drugs such as
chloroquine act by blocking the removal of haem from the parasite, thus causing
it to be poisoned by its own waste. Chloroquine resistance appears to result
from the ability of the parasite to exclude the drug from the site where haem
processing occurs and not from any fundamental change in the way in which the
haem is processed. This means that if we understand how this haem is dealt with
in the parasite, we should be able to design successor drugs to chloroquine
which retain activity against the parasite based on the same, very successful
mechanism of action.
The actual process was recently investigated as a large multidisciplinary team.
The team was made up of pharmacologists Jill Combrinck, Joanne Egan, Pete Smith,
Dale Taylor, Donelly van Schalkwyk and Jason Walden, an electron microscopist,
Trevor Sewell (all at the University of Cape Town), physicists Giovanni Hearne
and Skhumbuzo Ntenteni (University of the Witwatersrand) and chemists Helder
Marques (University of the Witwatersrand) and Tim Egan.
The team showed
unequivocally that virtually all of the haem is indeed incorporated into malaria
pigment in Plasmodium falciparum. The results have been published as an
accelerated communication in the Biochemical Journal (UK). This process should
thus be of primary interest in the design of new drugs that have a similar mode
of action to chloroquine. As the structure of malaria pigment was finally
reported in 2000 by Scott Bohle and co-workers in America the basic information
for design of new drugs is now available. Of course, it is still a long road
from this basic knowledge to new drugs, a road made even more difficult by the
need to ensure eventual affordability of any new antimalarial drug.
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