The above article about Chagas' disease and space missions by Dinah Eng appeared on page 13 of the International Herald Tribune of 30 November 2000.
Some more background information on
the technical aspects of the experiments in this article is
given here by Fred
Opperdoes 3-D structure of Trypanosome
glyceraldehydephosphate dehydrogenase (GAPDH, 1GGA.PDB).
Created with PDB
to Animated Gif
Trypanosomatidae are all without exception
parasitic and some cause important disease, such as Chagas' disease
in humans in the rural areas of Central and South America, which
kills about 45,000 people a year, sleeping sickness in Tropical
Africa, responsible for an estimated 300.000 fatal cases per year and
leishmaniasis in most tropical and subtropical parts of the world,
responsible for some 12 million infected people and an estimated
hundred thousand deaths per year. Few drugs are available for the
treatment of these diseases and many are not without side effects.
Also an increasing drug resistance of the parasites causes great
concern for the future. Several laboratories have now engaged in the
development of new and better drugs for these diseases of the poor.
The glycolytic pathway of the trypanosomatid parasites causing these
diseases is considered an excellent drug target. Biochemists in
Brussels (Belgium) and protein crystallographers in Seattle (USA) and
in Sao Carlos in Brazil, have since 1985 studied the glycolytic
enzymes of these parasites in great detail with the aim of developing
specific drugs that interfere with the their functioning and so may
lead to a rapid cure for trypanosomiasis and leishmaniasis. Studies
on the glyceraldehydephosphate dehydrogenase (GAPDH) of
Trypanosoma brucei and the related parasites Leishmania
mexicana and Trypanosoma cruzi have revealed that
especially this enzyme would be a very good
drug target indeed. However, drug
development depends of a detailed knowledge of the differences in
three-dimensional structure of the target enzyme and the
corresponding enzyme of the human host. Therefore, the crystal
structures of all three parasite enzymes and of the human enzyme had
to be solved. The Leishmania
and T.
brucei enzymes were crystallized
using conventional techniques in the laboratory. However, the T.
cruzi enzyme was taken on board of the space shuttle in 1996 for
crystallization experiments. For this experiment the enzyme GAPDH was
first brought to overexpression
in the bacterium Escherichia
coli by Véronique Hannaert and Paul Michels in the group
of Fred Opperdoes in Brussels. Then the purified enzyme was produced
in large quantities in the laboratory of Glaucius Oliva at the
University of Sao Paulo in Sao Carlos, Brazil. This protein was then
crystallized in space under conditions of micro gravity. In the first
experiment in 1996, they tried to get better diffracting crystals of
the protein made by the parasite, but the flight proved too short.
Experiments were continued on later flights. In NASA Space Shuttle
mission STS-91 in May 1998 crystallization of T. cruzi GAPDH with
flavone
inhibitors isolated from the Brazilian
plant Neoraputia magnifica was attempted, but only a structure
of the enzyme in complex with a coumarine inhibitor was obtained. The
strategy is to find a substance that will bind with a protein made by
the parasite and keep it from multiplying. Finally a high
resolution structure of this protein
was obtained by the Brazilian crystallographers. The other protein
crystallographers of the Howard Hughes institute in Seattle (USA) in
collaboration with chemists at the University of Washington and
working with the same enzyme but from the related parasites T.
brucei and Leishmania mexicana, succeeded to synthesize
a
highly specific drug that inhibited the
parasite enzyme but not the corresponding enzyme of the host. This
drug was then tested on live parasites and turned out to kill both
T. cruzi, T. brucei and L. mexicana, without affecting
the human host cells. This story demonstrates how scientists when
they join all possible efforts may succeed in developing new drugs
that can be of benefit to the poorest people.
Created by Fred
R. Opperdoes on 5 Dec,
2000