Antiparasitic chemotherapy: tinkering with the purine salvage pathway

Distinguishable differences between infectine organisms and their respective hosts with respect to metabolism and macromolecular structure provide scopes for detailed characterization of target proteins and/or macromolecules as the focus for the development of selective inhibitors. In order to develop a rational approach to antiparasitic chemotherapy, finding differences in the biochemical pathways of the parasite with respect to the host it infects is therefore of primary importance. Like most parasitic protozoan, the genus Leishmania is an obligate auxotroph of purines and hence for requirement of purine bases depends on its own purine salvage pathways. Among various purine acquisition routes used by the parasite, the pathway involved in assimilation of adenosine nucleotide is unique and differs significantly in the extracellular form of the parasite (promastigotes) from its corresponding intracellular form (amastigotes). Adenosine kinase (AdK) is the gateway enzyme of this pathway and displays stage-specific activity pattern. Therefore, understanding the catalytic mechanism of the enzyme, its structural complexities and mode of its regulation have emerged as one of the major areas of investigation. This review, in general, discusses possible strategies to validate several purine salvage enzymes as targets for chemotherapeutic manipulation with special reference to adenosine kinase of Leishmania donovani. Systemic endotheliosis, commonly known as Kala-azar in India, is caused by the parasitic protozoon Leishmania donovani. The spread of leishmaniases follows the distribution of these vectors in the temperate, tropical and subtropical regions of the world leading to loss of thousands of human lives.' WHO has declared leishmaniasis among one of the six major diseases namely leishmaniasis, malaria, amoebiasis, filariasis, Chagas disease and schistosomiasis in its Special Programme for Research and Training in Tropical Diseases. Strategies for better prophylaxis and urgent therapies must be therefore devised to control this menace among poor and under privileged population. However, the possible availability of antiparasitic vaccines appears remote in near future. Therefore, chemotherapy remains the mainstay for the treatment of most parasitic diseases. Selectivity of an antiparasitic compound must depend upon its mode of specific inhibition of parasite replication leaving host processes unaffected. In principle, these agents are expected to exert their selective actions against growth of the invading organisms by having one or both of the following properties: (i) Selective activation of compounds in question by enzyme (s) from the invading organisms, which are not present in the uninfected cells. (ii) Selective inhibition of vital enzyme(s), which are essential for replication of the parasites. In order to design specific compounds with the above characteristics, it is essential to have a thorough knowledge of the properties of the enzyme(s) and/or macromolecules which are unique to the parasite. Phylogenetic studies suggested that trypanosomatid parasites are relatively early-branching eukaryotic cells and indeed their cellular organization differs considerably from their mammalian hosts counterpart. Various enzymes, metabolites or proteins identified in parasites and known to be absent from or strikingly different in the mammalian hosts were considered as ideal drug targets. Among the various metabolic pathways that are presently being studied for their prospects to be exploited as the target for chemotherapeutic manipulation, the most important are (i) purine salvage (ii) polyamine and thiol metabolism (iii) folate biosynthesis (iv) DNA replication (v) glycolytic and (vi) fatty acid biosynthetic pathways etc. A number of excellent reviews, describing the prospects and efficacies of these pathways, already exist in the literature. Our laboratory is engaged in studying the pathways responsible for synthesis and assimilation ofpurine nucleotides in the parasitic protozoon Leishmania donovani. Therefore, we shall, for the constraint of space, try to restrict the discussion mostly with the purine salvage pathways of various Leishmania parasites with particular reference to the unique features of one of the enzymes of the purine salvage pathway viz AdK and its prospects as the chemotherapeutic target. However, contributions of other workers will also be discussed whenever essential and analogy will be drawn in order to make the reading coherent. The Leishmania genus goes through a dimorphic life cycle. It exists as a promastigote (extracellular form) in the sand fly vector but is converted to an amastigote (intracellular form) upon entry into mammalian macrophages. During this transformation process, the activities of a large number of proteins and/or enzymes have been reported to be stage-specifically altered and hence they could be prospective targets for development of chemotherapeutic regimen based on the exploitable differences of the parasitic proteins from their respective host counterpart.