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Sleeping sickness has been largely ignored by the pharmaceutical industry because the poor
socioeconomic situation in the part of the African continent afflicted by this debilitating disease offers
little prospect of reasonable financial returns [8]. It is revealing that eflornithine was originally
developed as an anticancer drug. It was screened for antitrypanosomal properties only when the
biochemistry of the trypanosomal polyamine metabolism was understood [9]. Fortunately, the cell
biology of trypanosomes is so extraordinary that they have been the subject of more fundamental
research than most other protozoan parasites [5]. Each of these unique features of T. brucei may become
a target for new drugs, provided they prove to be essential for the survival of the parasite in the human
host. With such a wealth of biochemical information, structure-based drug design provides a tremendous
opportunity to arrive at new drugs to cure sleeping sickness.
B. Targets for Future Drugs
Preventing trypanosomiasis would be a nobler goal than curing it. Unfortunately, trypanosomes are
experts in evading our immune system. They achieve this by varying their dense surface coat. It is
composed of ten million copies of a single protein, the variant surface glycoprotein (VSG), for which
they have no less than a thousand different genes. In this way trypanosomes can change surface antigens
more rapidly than the host can produce new antibodies [10]. Clearly, such a mechanism leaves little
hope for preventing sleeping sickness by vaccination.
In contrast to the small number of drugs available to treat trypanosomiasis, the opportunities for
developing new drugs are ample, as can be seen from Table 1. They range from unique RNA processing
to reduced metabolism, salvage systems, and different rates of protein turnover. All of these features
were the subject of an outstanding review by C.C. Wang [5].
An inventory of the structural information waiting to be exploited by structure-based drug design reveals
eight potential target enzymes (Table 2). Since for most trypanosomatid proteins there is a human
counterpart it is mandatory that designed inhibitors be selective, i.e., have very little affinity for the
equivalent enzymes of the human host. As a consequence, selective design requires pairs of equivalent
structures from the parasite and from the host. A complication for selective design is that for three of the
mammalian enzymes only the structure of one isoenzyme is known. For example, the structure of human
aldolase A has been determined [23] but not the structures of isoenzymes B and C, which share only 69
and 82% sequence identity to isoenzyme A [40–42]. Of course, homology modeling might be a way to
overcome this problem.
From Table 2 it is evident that only for three proteins, TIM, GAPDH, and trypanothione reductase the
structures of the parasite and host enzymes are
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