Inhibitors of the Purine Salvage Pathway: A Valuable Approach for Antiprotozoal Chemotherapy?

Abstract

For many years, the purine salvage pathway of parasitic protozoa has been regarded as an attractive chemotherapeutic target. Parasitic protozoa lack de novo synthesis and rely entirely on the purine salvage pathway to meet their purine demands. Because of the great phylogenetic difference between parasite and host, there are often sufficient distinctions that can be exploited to design specific inhibitors for the parasitic enzymes. As a result, this pathway has been thoroughly investigated over the last twenty years. It is only quite recently that the genome studies of Trypanosoma, Leishmania and Plasmodium have been published. Based on these genomic data however, the existence of by-pass mechanisms by other enzymes and transporter systems could be suggested. Taking into account such proposition, the question might arise as to whether inhibition of a single salvage enzyme will be able or not to cause parasite death or growth arrest. In this paper, the key enzymes in the purine salvage pathways of relevant pathogenic species from the genera Trypanosoma, Leishmania and Plasmodium are reviewed. Their potential as drug targets is critically evaluated and where possible, correlated to literature data on antiparasitic activity of their inhibitors. While many studies over the past ten years have yielded contradictory results, this review attempts to clarify these findings by discussing the latest elements of progress in the field. Additionally, as part of a broader discussion on substrate analogue types of inhibitors, special attention is paid to iminoribitol derivatives, serving as transition state analogues of nucleoside-processing enzymes and comprising the most potent inhibitors reported for purine salvage enzymes. More specifically, the development of three generations of immucillins and a newer series of N-(arylmethyl-) substituted iminoribitol derivatives will be discussed. Finally, this review also covers subversive substrates of salvage enzymes: compounds that are transformed by enzymatic activity into cytotoxic agents. Although not by directly intervening in the process of purine recovery, the subversive substrate approach might deliver antiprotozoal compounds that rely on salvage enzymes for their activity.

Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations

“…Interestingly, the corresponding metabolite pyrroline-5-carboxylate was found to be increased in our study. Martin et al (54) also showed that purine starvation augmented the interconversion of hypoxanthine and ampicillin (AMP) to imipenem (IMP), both key nucleotides of the purine salvage pathway of L. donovani (55). High levels of hypoxanthine were also found in the resistant lines of our study (IMP and AMP were not detected).…”

Immucillins in Infectious Diseases

“…The purine base is available for salvage by phosphoribosyltransferases, in both the host and the parasite. 25–27 The purine phosphoribosyltransferase from P. falciparum accepts hypoxanthine, guanine, and xanthine, in decreasing order of physiological significance. 28,29 Their products are purine nucleoside monophosphates, and these serve as precursors for conversion to all purines as RNA and DNA precursors (Figure 2).…”

Delivering on Promises? The Impact of Kinetoplastid Genomics on Sleeping Sickness, Chagas Disease and Leishmaniasis

“…25 However, based on the genome sequence data, it seems that trypanosomatids possess by-pass mechanisms involving other enzymes and transporters. 26 This poses the question as to whether inhibition of a single enzyme of the purine salvage pathway is enough to kill trypanosomatids or whether inhibition of multiple enzymes by combination therapy would be required.…”