Antiparasitic Chemotherapy:

Abstract

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 stu...

Metabolic Reprogramming during Purine Stress in the Protozoan Pathogen Leishmania donovani

“…Leishmania , like all parasitic protozoa characterized to date, are auxotrophic for purines and have evolved a unique set of purine transporters and salvage enzymes to scavenge these essential nutrients from their host [21]–[23]. Because purine acquisition in Leishmania is an indispensable nutritional process, and the pathway is considered an attractive target for therapeutic exploration, the components of purine salvage have been extensively characterized at the molecular, biochemical, and, in some cases, at the structural level [21], [23]–[27]. However, the regulation of this pathway in response to changes in the extracellular purine milieu is poorly understood.…”

Expression and purification of an engineered, yeast-expressedLeishmania donovaninucleoside hydrolase with immunogenic properties

“…7 Leishmania parasites are hence dependent on exogenous purines provided by their host. 7,8 In order to metabolize host purine nucleosides, the Leishmania purine salvage pathway utilizes LdNH36 as an essential nucleoside hydrolase. 9 The hydrolase has been detected on the cell surface in both promastigote and amastigote forms of L. donovani.…”

Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

“…Leishmania donovani lacks the ability to synthesize purines de novo and thus is well known to be purine auxotroph [7, 8]. Reports from different authors have revealed the importance of this enzyme in most eukaryotic cells and especially in the purine-auxotrophic parasitic protozoa.…”