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Document Page 367 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 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_367.html [4/5/2004 5:31:49 PM]
Document Table 1 Trypanosomal Targets, Their Human Equivalents, and Current Leads for Drug Design T. brucei Human host Lead RNA editing by trans-splicing [11] cis-splicing none All energy from fast glycolysis [12] glycolysis and oxidative phosphorylation Glucose transporter [14] human erythrocyte glucose transporter Purine P2 transporter [15] none Purine salvage enzymes, e.g., HGPRT b [16] HGPRT none Slow rate of enzyme turnover [17], e.g., ornithine decarboxylase [18] Polyamine metabolism, e.g., S-adenosyl methionine decarboxylase [19] MMBA a [13] none Page 368 fast rate of enzyme turnover eflornithine (= drug) [9] S-adenosyl methionine decarboxylase MDL 73811 c Trypanothione reductase [20] glutathione reductase mepacrine VSG anchor: a myristate-containing GPI [21] 10-(propoxy)-decanoate d a MMBA = 2' -deoxy-2' -(m-methoxybenzamido)-adenosine. b HGPRT = hypoxanthine guanine phosphoribosyltransferase. c MDL 73811 = 5' -{[(Z)-4-amino-2-butenyl]methylamino}-5' -deoxyadenosine. dIt has not been established whether the trypanocidal effect of this compound is due to its incorporation in the GPI anchor [5]. known. For five more targets the crystal structure of only the mammalian enzyme is available. Efforts to solve the structures of trypanosmatid aldolase, PGK, and PK counterparts are underway in our lab. This review explains how we attempted to arrive at selective inhibitors of three trypanosomal glycolytic enzymes. C. Trypanosomal Glycolysis: Enzyme Inhibition as a Target In the bloodstream of the human host, trypanosomes are metabolically http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_368.html (1 of 2) [4/5/2004 5:32:08 PM]
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